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2. Imbalanced Subthreshold Currents Following Sepsis and Chemotherapy: A Shared Mechanism Offering a New Therapeutic Target?

Author

Timothy C. Cope, Stephen N. Housley, Randall K. Powers, Paul Nardelli, and Mark M. Rich

Subjects
Oncology, medicine.medical_specialty, medicine.medical_treatment, Encephalopathy, Action Potentials, Ion Channels, Article, Sepsis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Animals, Humans, Fatigue, Motor Neurons, Chemotherapy, Brain Diseases, Subthreshold conduction, Mechanism (biology), business.industry, musculoskeletal, neural, and ocular physiology, General Neuroscience, Cancer, Peripheral Nervous System Diseases, medicine.disease, Oxaliplatin, Rats, nervous system, 030220 oncology & carcinogenesis, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Both sepsis and treatment of cancer with chemotherapy are known to cause neurologic dysfunction. The primary defects seen in both groups of patients are neuropathy and encephalopathy; the underlying mechanisms are poorly understood. Analysis of preclinical models of these disparate conditions reveal similar defects in ion channel function contributing to peripheral neuropathy. The defects in ion channel function extend to the central nervous system where lower motoneurons are affected. In motoneurons the defect involves ion channels responsible for subthreshold currents that convert steady depolarization into repetitive firing. The inability to correctly translate depolarization into steady, repetitive firing has profound effects on motor function, and could be an important contributor to weakness and fatigue experienced by both groups of patients. The possibility that disruption of function, either instead of, or in addition to neurodegeneration, may underlie weakness and fatigue leads to a novel approach to therapy. Activation of serotonin (5HT) receptors in a rat model of sepsis restores the normal balance of subthreshold currents and normal motoneuron firing. If an imbalance of subthreshold currents also occurs in other central nervous system neurons, it could contribute to encephalopathy. We hypothesize that pharmacologically restoring the proper balance of subthreshold currents might provide effective therapy for both neuropathy and encephalopathy in patients recovering from sepsis or treatment with chemotherapy.

Published
2023

7. Data from Cancer Exacerbates Chemotherapy-Induced Sensory Neuropathy

Author

Timothy C. Cope, John F. McDonald, Lilya V. Matyunina, Emily Pfahl, Travis M. Rotterman, Dario I. Carrasco, Paul Nardelli, and Stephen N. Housley

Abstract

For the constellation of neurologic disorders known as chemotherapy-induced peripheral neuropathy, mechanistic understanding and treatment remain deficient. Here, we present the first evidence that chronic sensory neuropathy depends on nonlinear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism, and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as one potential contributor to sensory neuron dysfunction. Validated measures of sensorimotor behavior in awake, behaving animals revealed dysfunction after chronic chemotherapy treatment was exacerbated by cancer. Notably, errors in precise forelimb placement emerged as a novel behavioral deficit unpredicted by our previous study of chemotherapy alone. These original findings identify novel contributors to peripheral neuropathy and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer.Significance:These findings highlight the need to account for pathobiological interactions between cancer and chemotherapy as a major contributor to neuropathy and will have significant and immediate impact on future investigations in this field.

Published
2023
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8. Activation of the CA2-ventral CA1 pathway reverses social discrimination dysfunction in Shank3B knockout mice

Author

Elise C. Cope, Samantha H. Wang, Renée C. Waters, Isha R. Gore, Betsy Vasquez, Blake J. Laham, and Elizabeth Gould

Subjects
Multidisciplinary, General Physics and Astronomy, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract

Mutation or deletion of the SHANK3 gene, which encodes a synaptic scaffolding protein, is linked to autism spectrum disorder and Phelan-McDermid syndrome, conditions associated with social memory impairments. Shank3B knockout mice also exhibit social memory deficits. The CA2 region of the hippocampus integrates numerous inputs and sends a major output to the ventral CA1 (vCA1). Despite finding few differences in excitatory afferents to the CA2 in Shank3B knockout mice, we found that activation of CA2 neurons as well as the CA2-vCA1 pathway restored social recognition function to wildtype levels. vCA1 neuronal oscillations have been linked to social memory, but we observed no differences in these measures between wildtype and Shank3B knockout mice. However, activation of the CA2 enhanced vCA1 theta power in Shank3B knockout mice, concurrent with behavioral improvements. These findings suggest that stimulating adult circuitry in a mouse model with neurodevelopmental impairments can invoke latent social memory function.

Published
2023
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9. Biophysical model of muscle spindle encoding

Author

Stephen N. Housley, Randal K. Powers, Paul Nardelli, Sebinne Lee, Kyle Blum, Guy S. Bewick, Robert W. Banks, and Timothy C. Cope

Subjects
Nutrition and Dietetics, Physiology, Physiology (medical), General Medicine
Abstract

Muscle spindles encode mechanosensory information by mechanisms that remain only partially understood. Their complexity is expressed in mounting evidence of various molecular mechanisms that play essential roles in muscle mechanics, mechanotransduction and intrinsic modulation of muscle spindle firing behaviour. Biophysical modelling provides a tractable approach to achieve more comprehensive mechanistic understanding of such complex systems that would be difficult/impossible by more traditional, reductionist means. Our objective here was to construct the first integrative biophysical model of muscle spindle firing. We leveraged current knowledge of muscle spindle neuroanatomy and in vivo electrophysiology to develop and validate a biophysical model that reproduces key in vivo muscle spindle encoding characteristics. Crucially, to our knowledge, this is the first computational model of mammalian muscle spindle that integrates the asymmetric distribution of known voltage-gated ion channels (VGCs) with neuronal architecture to generate realistic firing profiles, both of which seem likely to be of great biophysical importance. Results predict that particular features of neuronal architecture regulate specific characteristics of Ia encoding. Computational simulations also predict that the asymmetric distribution and ratios of VGCs is a complementary and, in some instances, orthogonal means to regulate Ia encoding. These results generate testable hypotheses and highlight the integral role of peripheral neuronal structure and ion channel composition and distribution in somatosensory signalling.

Published
2023
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10. Detection of epimuscular myofascial forces by Golgi tendon organs

Author

Timothy C. Cope, Hiltsje A. Smilde, Jacob A. Vincent, Huub Maas, Wendy Noort, Paul Nardelli, Neuromechanics, AMS - Musculoskeletal Health, and AMS - Tissue Function & Regeneration

Subjects
Sensory system, Primary afferent, Tendons, symbols.namesake, medicine, Animals, Humans, Rats, Wistar, Golgi tendon organ, Muscle, Skeletal, Proprioception, Chemistry, General Neuroscience, Anatomy, Golgi apparatus, musculoskeletal system, Skeleton (computer programming), Biomechanical Phenomena, Rats, Tendon, medicine.anatomical_structure, symbols, Rat, Tendon organ, Mechanoreceptors, Research Article, Muscle Contraction, Lateral gastrocnemius, Myofascial force transmission
Abstract

Skeletal muscles embed multiple tendon organs, both at the proximal and distal ends of muscle fibers. One of the functions of such spatial distribution may be to provide locally unique force feedback, which may become more important when stresses are distributed non-uniformly within the muscle. Forces exerted by connections between adjacent muscles (i.e. epimuscular myofascial forces) may cause such local differences in force. The aim of this exploratory study was to investigate the effects of mechanical interactions between adjacent muscles on sensory encoding by tendon organs. Action potentials from single afferents were recorded intra-axonally in response to ramp-hold release (RHR) stretches of a passive agonistic muscle at different lengths or relative positions of its passive synergist. The tendons of gastrocnemius (GAS), plantaris (PL) and soleus (SO) muscles were cut from the skeleton for attachment to servomotors. Connective tissues among these muscles were kept intact. Lengthening GAS + PL decreased the force threshold of SO tendon organs (p = 0.035). The force threshold of lateral gastrocnemius (LG) tendon organs was not affected by SO length (p = 0.371). Also displacing LG + PL, kept at a constant muscle–tendon unit length, from a proximal to a more distal position resulted in a decrease in force threshold of LG tendon organs (p = 0.007). These results indicate that tendon organ firing is affected by changes in length and/or relative position of adjacent synergistic muscles. We conclude that tendon organs can provide the central nervous system with information about local stresses caused by epimuscular myofascial forces.

Published
2022
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11. Effects of route of administration on neural exposure to platinum-based chemotherapy treatment: a pharmacokinetic study in rat

Author

Stephen N. Housley, Dario I. Carrasco, Paul Nardelli, Laura O'Farrell, Timothy C. Cope, Richard K. Noel, and Travis M. Rotterman

Subjects
Antineoplastic Agents, Platinum Compounds, Pharmacology, Toxicology, Article, Route of administration, Bolus (medicine), Pharmacokinetics, In vivo, Ganglia, Spinal, medicine, Animals, Distribution (pharmacology), Infusions, Parenteral, Dosing, business.industry, Drug Administration Routes, General Neuroscience, Neurotoxicity, medicine.disease, Rats, Inbred F344, Rats, Oxaliplatin, Administration, Intravenous, business, medicine.drug
Abstract

The persisting need for effective clinical treatment of chemotherapy-induced neurotoxicity (CIN) motivates critical evaluation of preclinical models of CIN for their translational relevance. The present study aimed to provide the first quantitative evaluation of neural tissue exposed in vivo to a platinum-based anticancer compound, oxaliplatin (OX) during and after two commonly used dosing regimens: slow IV infusion used clinically and bolus IP injection used preclinically. Inductively-coupled plasma mass spectrometry analysis of dorsal root ganglia indicated that while differences in the temporal dynamics of platinum distribution exist, key drivers of neurotoxicity, e.g. peak concentrations and exposure, were not different across the two routes of administration. We conclude that the IP route of OX administration achieves clinically relevant pharmacokinetic exposure of neural tissues in a rodent model of CIN.

Published
2021
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12. Impact of diabetes on the management and outcomes in atrial fibrillation:an analysis from the ESC-EHRA EORP-AF Long-Term General Registry

Author

Wern Yew Ding, Agnieszka Kotalczyk, Giuseppe Boriani, Francisco Marin, Carina Blomström-Lundqvist, Tatjana S. Potpara, Laurent Fauchier, Gregory.Y.H. Lip, G. Boriani, G.Y.H. Lip, L. Tavazzi, A.P. Maggioni, G.-A. Dan, T. Potpara, M. Nabauer, F. Marin, Z. Kalarus, A. Goda, G. Mairesse, T. Shalganov, L. Antoniades, M. Taborsky, S. Riahi, P. Muda, I. García Bolao, O. Piot, K. Etsadashvili, E. Simantirakis, M. Haim, A. Azhari, J. Najafian, M. Santini, E. Mirrakhimov, K.A. Kulzida, A. Erglis, L. Poposka, M. Burg, H. Crijns, Ö. Erküner, D. Atar, R. Lenarczyk, M. Martins Oliveira, D. Shah, E. Serdechnaya, E. Diker, D. Lane, E. Zëra, U. Ekmekçiu, V. Paparisto, M. Tase, H. Gjergo, J. Dragoti, M. Ciutea, N. Ahadi, Z. el Husseini, M. Raepers, J. Leroy, P. Haushan, A. Jourdan, C. Lepiece, L. Desteghe, J. Vijgen, P. Koopman, G. Van Genechten, H. Heidbuchel, T. Boussy, M. De Coninck, H. Van Eeckhoutte, N. Bouckaert, A. Friart, J. Boreux, C. Arend, P. Evrard, L. Stefan, E. Hoffer, J. Herzet, M. Massoz, C. Celentano, M. Sprynger, L. Pierard, P. Melon, B. Van Hauwaert, C. Kuppens, D. Faes, D. Van Lier, A. Van Dorpe, A. Gerardy, O. Deceuninck, O. Xhaet, F. Dormal, E. Ballant, D. Blommaert, D. Yakova, M. Hristov, T. Yncheva, N. Stancheva, S. Tisheva, M. Tokmakova, F. Nikolov, D. Gencheva, B. Kunev, M. Stoyanov, D. Marchov, V. Gelev, V. Traykov, A. Kisheva, H. Tsvyatkov, R. Shtereva, S. Bakalska-Georgieva, S. Slavcheva, Y. Yotov, M. Kubíčková, A. Marni Joensen, A. Gammelmark, L. Hvilsted Rasmussen, P. Dinesen, S. Krogh Venø, B. Sorensen, A. Korsgaard, K. Andersen, C. Fragtrup Hellum, A. Svenningsen, O. Nyvad, P. Wiggers, O. May, A. Aarup, B. Graversen, L. Jensen, M. Andersen, M. Svejgaard, S. Vester, S. Hansen, V. Lynggaard, M. Ciudad, R. Vettus, A. Maestre, S. Castaño, S. Cheggour, J. Poulard, V. Mouquet, S. Leparrée, J. Bouet, J. Taieb, A. Doucy, H. Duquenne, A. Furber, J. Dupuis, J. Rautureau, M. Font, P. Damiano, M. Lacrimini, J. Abalea, S. Boismal, T. Menez, J. Mansourati, G. Range, H. Gorka, C. Laure, C. Vassalière, N. Elbaz, N. Lellouche, K. Djouadi, F. Roubille, D. Dietz, J. Davy, M. Granier, P. Winum, C. Leperchois-Jacquey, H. Kassim, E. Marijon, J. Le Heuzey, J. Fedida, C. Maupain, C. Himbert, E. Gandjbakhch, F. Hidden-Lucet, G. Duthoit, N. Badenco, T. Chastre, X. Waintraub, M. Oudihat, J. Lacoste, C. Stephan, H. Bader, N. Delarche, L. Giry, D. Arnaud, C. Lopez, F. Boury, I. Brunello, M. Lefèvre, R. Mingam, M. Haissaguerre, M. Le Bidan, D. Pavin, V. Le Moal, C. Leclercq, T. Beitar, I. Martel, A. Schmid, N. Sadki, C. Romeyer-Bouchard, A. Da Costa, I. Arnault, M. Boyer, C. Piat, N. Lozance, S. Nastevska, A. Doneva, B. Fortomaroska Milevska, B. Sheshoski, K. Petroska, N. Taneska, N. Bakrecheski, K. Lazarovska, S. Jovevska, V. Ristovski, A. Antovski, E. Lazarova, I. Kotlar, J. Taleski, S. Kedev, N. Zlatanovik, S. Jordanova, T. Bajraktarova Proseva, S. Doncovska, D. Maisuradze, A. Esakia, E. Sagirashvili, K. Lartsuliani, N. Natelashvili, N. Gumberidze, R. Gvenetadze, N. Gotonelia, N. Kuridze, G. Papiashvili, I. Menabde, S. Glöggler, A. Napp, C. Lebherz, H. Romero, K. Schmitz, M. Berger, M. Zink, S. Köster, J. Sachse, E. Vonderhagen, G. Soiron, K. Mischke, R. Reith, M. Schneider, W. Rieker, D. Boscher, A. Taschareck, A. Beer, D. Oster, O. Ritter, J. Adamczewski, S. Walter, A. Frommhold, E. Luckner, J. Richter, M. Schellner, S. Landgraf, S. Bartholome, R. Naumann, J. Schoeler, D. Westermeier, F. William, K. Wilhelm, M. Maerkl, R. Oekinghaus, M. Denart, M. Kriete, U. Tebbe, T. Scheibner, M. Gruber, A. Gerlach, C. Beckendorf, L. Anneken, M. Arnold, S. Lengerer, Z. Bal, C. Uecker, H. Förtsch, S. Fechner, V. Mages, E. Martens, H. Methe, T. Schmidt, B. Schaeffer, B. Hoffmann, J. Moser, K. Heitmann, S. Willems, C. Klaus, I. Lange, M. Durak, E. Esen, F. Mibach, H. Mibach, A. Utech, M. Gabelmann, R. Stumm, V. Ländle, C. Gartner, C. Goerg, N. Kaul, S. Messer, D. Burkhardt, C. Sander, R. Orthen, S. Kaes, A. Baumer, F. Dodos, A. Barth, G. Schaeffer, J. Gaertner, J. Winkler, A. Fahrig, J. Aring, I. Wenzel, S. Steiner, A. Kliesch, E. Kratz, K. Winter, P. Schneider, A. Haag, I. Mutscher, R. Bosch, J. Taggeselle, S. Meixner, A. Schnabel, A. Shamalla, H. Hötz, A. Korinth, C. Rheinert, G. Mehltretter, B. Schön, N. Schön, A. Starflinger, E. Englmann, G. Baytok, T. Laschinger, G. Ritscher, A. Gerth, D. Dechering, L. Eckardt, M. Kuhlmann, N. Proskynitopoulos, J. Brunn, K. Foth, C. Axthelm, H. Hohensee, K. Eberhard, S. Turbanisch, N. Hassler, A. Koestler, G. Stenzel, D. Kschiwan, M. Schwefer, S. Neiner, S. Hettwer, M. Haeussler-Schuchardt, R. Degenhardt, S. Sennhenn, M. Brendel, A. Stoehr, W. Widjaja, S. Loehndorf, A. Logemann, J. Hoskamp, J. Grundt, M. Block, R. Ulrych, A. Reithmeier, V. Panagopoulos, C. Martignani, D. Bernucci, E. Fantecchi, I. Diemberger, M. Ziacchi, M. Biffi, P. Cimaglia, J. Frisoni, I. Giannini, S. Boni, S. Fumagalli, S. Pupo, A. Di Chiara, P. Mirone, F. Pesce, C. Zoccali, V.L. Malavasi, A. Mussagaliyeva, B. Ahyt, Z. Salihova, K. Koshum-Bayeva, A. Kerimkulova, A. Bairamukova, B. Lurina, R. Zuzans, S. Jegere, I. Mintale, K. Kupics, K. Jubele, O. Kalejs, K. Vanhear, M. Cachia, E. Abela, S. Warwicker, T. Tabone, R. Xuereb, D. Asanovic, D. Drakalovic, M. Vukmirovic, N. Pavlovic, L. Music, N. Bulatovic, A. Boskovic, H. Uiterwaal, N. Bijsterveld, J. De Groot, J. Neefs, N. van den Berg, F. Piersma, A. Wilde, V. Hagens, J. Van Es, J. Van Opstal, B. Van Rennes, H. Verheij, W. Breukers, G. Tjeerdsma, R. Nijmeijer, D. Wegink, R. Binnema, S. Said, S. Philippens, W. van Doorn, T. Szili-Torok, R. Bhagwandien, P. Janse, A. Muskens, M. van Eck, R. Gevers, N. van der Ven, A. Duygun, B. Rahel, J. Meeder, A. Vold, C. Holst Hansen, I. Engset, B. Dyduch-Fejklowicz, E. Koba, M. Cichocka, A. Sokal, A. Kubicius, E. Pruchniewicz, A. Kowalik-Sztylc, W. Czapla, I. Mróz, M. Kozlowski, T. Pawlowski, M. Tendera, A. Winiarska-Filipek, A. Fidyk, A. Slowikowski, M. Haberka, M. Lachor-Broda, M. Biedron, Z. Gasior, M. Kołodziej, M. Janion, I. Gorczyca-Michta, B. Wozakowska-Kaplon, M. Stasiak, P. Jakubowski, T. Ciurus, J. Drozdz, M. Simiera, P. Zajac, T. Wcislo, P. Zycinski, J. Kasprzak, A. Olejnik, E. Harc-Dyl, J. Miarka, M. Pasieka, M. Ziemińska-Łuć, W. Bujak, A. Śliwiński, A. Grech, J. Morka, K. Petrykowska, M. Prasał, G. Hordyński, P. Feusette, P. Lipski, A. Wester, W. Streb, J. Romanek, P. Woźniak, M. Chlebuś, P. Szafarz, W. Stanik, M. Zakrzewski, J. Kaźmierczak, A. Przybylska, E. Skorek, H. Błaszczyk, M. Stępień, S. Szabowski, W. Krysiak, M. Szymańska, J. Karasiński, J. Blicharz, M. Skura, K. Hałas, L. Michalczyk, Z. Orski, K. Krzyżanowski, A. Skrobowski, L. Zieliński, M. Tomaszewska-Kiecana, M. Dłużniewski, M. Kiliszek, M. Peller, M. Budnik, P. Balsam, G. Opolski, A. Tymińska, K. Ozierański, A. Wancerz, A. Borowiec, E. Majos, R. Dabrowski, H. Szwed, A. Musialik-Lydka, A. Leopold-Jadczyk, E. Jedrzejczyk-Patej, M. Koziel, M. Mazurek, K. Krzemien-Wolska, P. Starosta, E. Nowalany-Kozielska, A. Orzechowska, M. Szpot, M. Staszel, S. Almeida, H. Pereira, L. Brandão Alves, R. Miranda, L. Ribeiro, F. Costa, F. Morgado, P. Carmo, P. Galvao Santos, R. Bernardo, P. Adragão, G. Ferreira da Silva, M. Peres, M. Alves, M. Leal, A. Cordeiro, P. Magalhães, P. Fontes, S. Leão, A. Delgado, A. Costa, B. Marmelo, B. Rodrigues, D. Moreira, J. Santos, L. Santos, A. Terchet, D. Darabantiu, S. Mercea, V. Turcin Halka, A. Pop Moldovan, A. Gabor, B. Doka, G. Catanescu, H. Rus, L. Oboroceanu, E. Bobescu, R. Popescu, A. Dan, A. Buzea, I. Daha, G. Dan, I. Neuhoff, M. Baluta, R. Ploesteanu, N. Dumitrache, M. Vintila, A. Daraban, C. Japie, E. Badila, H. Tewelde, M. Hostiuc, S. Frunza, E. Tintea, D. Bartos, A. Ciobanu, I. Popescu, N. Toma, C. Gherghinescu, D. Cretu, N. Patrascu, C. Stoicescu, C. Udroiu, G. Bicescu, V. Vintila, D. Vinereanu, M. Cinteza, R. Rimbas, M. Grecu, A. Cozma, F. Boros, M. Ille, O. Tica, R. Tor, A. Corina, A. Jeewooth, B. Maria, C. Georgiana, C. Natalia, D. Alin, D. Dinu-Andrei, M. Livia, R. Daniela, R. Larisa, S. Umaar, T. Tamara, M. Ioachim Popescu, D. Nistor, I. Sus, O. Coborosanu, N. Alina-Ramona, R. Dan, L. Petrescu, G. Ionescu, C. Vacarescu, E. Goanta, M. Mangea, A. Ionac, C. Mornos, D. Cozma, S. Pescariu, E. Solodovnicova, I. Soldatova, J. Shutova, L. Tjuleneva, T. Zubova, V. Uskov, D. Obukhov, G. Rusanova, N. Isakova, S. Odinsova, T. Arhipova, E. Kazakevich, O. Zavyalova, T. Novikova, I. Riabaia, S. Zhigalov, E. Drozdova, I. Luchkina, Y. Monogarova, D. Hegya, L. Rodionova, V. Nevzorova, O. Lusanova, A. Arandjelovic, D. Toncev, L. Vukmirovic, M. Radisavljevic, M. Milanov, N. Sekularac, M. Zdravkovic, S. Hinic, S. Dimkovic, T. Acimovic, J. Saric, S. Radovanovic, A. Kocijancic, B. Obrenovic-Kircanski, D. Kalimanovska Ostric, D. Simic, I. Jovanovic, I. Petrovic, M. Polovina, M. Vukicevic, M. Tomasevic, N. Mujovic, N. Radivojevic, O. Petrovic, S. Aleksandric, V. Kovacevic, Z. Mijatovic, B. Ivanovic, M. Tesic, A. Ristic, B. Vujisic-Tesic, M. Nedeljkovic, A. Karadzic, A. Uscumlic, M. Prodanovic, M. Zlatar, M. Asanin, B. Bisenic, V. Vasic, Z. Popovic, D. Djikic, M. Sipic, V. Peric, B. Dejanovic, N. Milosevic, S. Backovic, A. Stevanovic, A. Andric, B. Pencic, M. Pavlovic-Kleut, V. Celic, M. Pavlovic, M. Petrovic, M. Vuleta, N. Petrovic, S. Simovic, Z. Savovic, S. Milanov, G. Davidovic, V. Iric-Cupic, D. Djordjevic, M. Damjanovic, S. Zdravkovic, V. Topic, D. Stanojevic, M. Randjelovic, R. Jankovic-Tomasevic, V. Atanaskovic, S. Antic, D. Simonovic, M. Stojanovic, S. Stojanovic, V. Mitic, V. Ilic, D. Petrovic, M. Deljanin Ilic, S. Ilic, V. Stoickov, S. Markovic, A. Mijatovic, D. Tanasic, G. Radakovic, J. Peranovic, N. Panic-Jelic, O. Vujadinovic, P. Pajic, S. Bekic, S. Kovacevic, A. García Fernandez, A. Perez Cabeza, M. Anguita, L. Tercedor Sanchez, E. Mau, J. Loayssa, M. Ayarra, M. Carpintero, I. Roldán Rabadan, M. Gil Ortega, A. Tello Montoliu, E. Orenes Piñero, S. Manzano Fernández, F. Marín, A. Romero Aniorte, A. Veliz Martínez, M. Quintana Giner, G. Ballesteros, M. Palacio, O. Alcalde, I. García-Bolao, V. Bertomeu Gonzalez, F. Otero-Raviña, J. García Seara, J. Gonzalez Juanatey, N. Dayal, P. Maziarski, P. Gentil-Baron, M. Koç, E. Onrat, I.E. Dural, K. Yilmaz, B. Özin, S. Tan Kurklu, Y. Atmaca, U. Canpolat, L. Tokgozoglu, A.K. Dolu, B. Demirtas, D. Sahin, O. Ozcan Celebi, G. Gagirci, U.O. Turk, H. Ari, N. Polat, N. Toprak, M. Sucu, O. Akin Serdar, A. Taha Alper, A. Kepez, Y. Yuksel, A. Uzunselvi, S. Yuksel, M. Sahin, O. Kayapinar, T. Ozcan, H. Kaya, M.B. Yilmaz, M. Kutlu, M. Demir, C. Gibbs, S. Kaminskiene, M. Bryce, A. Skinner, G. Belcher, J. Hunt, L. Stancombe, B. Holbrook, C. Peters, S. Tettersell, A. Shantsila, K. Senoo, M. Proietti, K. Russell, P. Domingos, S. Hussain, J. Partridge, R. Haynes, S. Bahadur, R. Brown, S. McMahon, J. McDonald, K. Balachandran, R. Singh, S. Garg, H. Desai, K. Davies, W. Goddard, G. Galasko, I. Rahman, Y. Chua, O. Payne, S. Preston, O. Brennan, L. Pedley, C. Whiteside, C. Dickinson, J. Brown, K. Jones, L. Benham, R. Brady, L. Buchanan, A. Ashton, H. Crowther, H. Fairlamb, S. Thornthwaite, C. Relph, A. McSkeane, U. Poultney, N. Kelsall, P. Rice, T. Wilson, M. Wrigley, R. Kaba, T. Patel, E. Young, J. Law, C. Runnett, H. Thomas, H. McKie, J. Fuller, S. Pick, A. Sharp, A. Hunt, K. Thorpe, C. Hardman, E. Cusack, L. Adams, M. Hough, S. Keenan, A. Bowring, J. Watts, J. Zaman, K. Goffin, H. Nutt, Y. Beerachee, J. Featherstone, C. Mills, J. Pearson, L. Stephenson, S. Grant, A. Wilson, C. Hawksworth, I. Alam, M. Robinson, S. Ryan, R. Egdell, E. Gibson, M. Holland, D. Leonard, B. Mishra, S. Ahmad, H. Randall, J. Hill, L. Reid, M. George, S. McKinley, L. Brockway, W. Milligan, J. Sobolewska, J. Muir, L. Tuckis, L. Winstanley, P. Jacob, S. Kaye, L. Morby, A. Jan, T. Sewell, C. Boos, B. Wadams, C. Cope, P. Jefferey, N. Andrews, A. Getty, A. Suttling, C. Turner, K. Hudson, R. Austin, S. Howe, R. Iqbal, N. Gandhi, K. Brophy, P. Mirza, E. Willard, S. Collins, N. Ndlovu, E. Subkovas, V. Karthikeyan, L. Waggett, A. Wood, A. Bolger, J. Stockport, L. Evans, E. Harman, J. Starling, L. Williams, V. Saul, M. Sinha, L. Bell, S. Tudgay, S. Kemp, L. Frost, T. Ingram, A. Loughlin, C. Adams, M. Adams, F. Hurford, C. Owen, C. Miller, D. Donaldson, H. Tivenan, H. Button, A. Nasser, O. Jhagra, B. Stidolph, C. Brown, C. Livingstone, M. Duffy, P. Madgwick, P. Roberts, E. Greenwood, L. Fletcher, M. Beveridge, S. Earles, D. McKenzie, D. Beacock, M. Dayer, M. Seddon, D. Greenwell, F. Luxton, F. Venn, H. Mills, J. Rewbury, K. James, K. Roberts, L. Tonks, D. Felmeden, W. Taggu, A. Summerhayes, D. Hughes, J. Sutton, L. Felmeden, M. Khan, E. Walker, L. Norris, L. O'Donohoe, A. Mozid, H. Dymond, H. Lloyd-Jones, G. Saunders, D. Simmons, D. Coles, D. Cotterill, S. Beech, S. Kidd, B. Wrigley, S. Petkar, A. Smallwood, R. Jones, E. Radford, S. Milgate, S. Metherell, V. Cottam, C. Buckley, A. Broadley, D. Wood, J. Allison, K. Rennie, L. Balian, L. Howard, L. Pippard, S. Board, T. Pitt-Kerby, Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Océan du Large et Variabilité Climatique (OLVAC), Laboratoire d'études en Géophysique et océanographie spatiales (LEGOS), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Uppsala University, University of Belgrade [Belgrade], CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Éducation Éthique Santé EA 7505 (EES), and Université de Tours (UT)

Subjects
Kardiologi, General Practice, Cohort, Anticoagulants, MACE, Endocrinology and Diabetes, Prognosis, [SHS]Humanities and Social Sciences, Allmänmedicin, Stroke, Risk Factors, Healthcare resource utilisation, Mortality, Prevalence, Endokrinologi och diabetes, Atrial Fibrillation, Internal Medicine, Diabetes Mellitus, Quality of Life, Humans, Cardiac and Cardiovascular Systems, Prospective Studies, Registries, Aged
Abstract

BACKGROUND: The prevalence of atrial fibrillation(AF) and diabetes mellitus is rising to epidemic proportions. We aimed to assess the impact of diabetes on the management and outcomes of patients with AF.METHODS: The EORP-AF General Long-Term Registry is a prospective, observational registry from 250 centres across 27 European countries. Outcomes of interest were as follows: i)rhythm control interventions; ii)quality of life; iii)healthcare resource utilisation; and iv)major adverse events.RESULTS: Of 11,028 patients with AF, the median age was 71 (63-77) years and 2537 (23.0%) had diabetes. Median follow-up was 24 months. Diabetes was related to increased use of anticoagulation but less rhythm control interventions. Using multivariable analysis, at 2-year follow-up, patients with diabetes were associated with greater levels of anxiety (p = 0.038) compared to those without diabetes. Overall, diabetes was associated with worse health during follow-up, as indicated by Health Utility Score and Visual Analogue Scale. Healthcare resource utilisation was greater with diabetes in terms of length of hospital stay (8.1 (±8.2) vs. 6.1 (±6.7) days); cardiology and internal medicine/general practitioner visits; and emergency room admissions. Diabetes was an independent risk factor of major adverse cardiovascular event (MACE; HR 1.26 [95% CI, 1.04-1.52]), all-cause mortality (HR 1.28 [95% CI, 1.08-1.52]), and cardiovascular mortality (HR 1.41 [95% CI, 1.09-1.83]).CONCLUSION: In this contemporary AF cohort, diabetes was present in 1 in 4 patients and it served as an independent risk factor for reduced quality of life, greater healthcare resource utilisation and excess MACE, all-cause mortality and cardiovascular mortality. There was increased use of anticoagulation therapy in diabetes but with less rhythm control interventions.

Published
2022
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13. Mechanosensory encoding dysfunction emerges from cancer-chemotherapy interaction

Author

Stephen N. Housley, Paul Nardelli, Travis M. Rotterman, J’Ana Reed, and Timothy C. Cope

Subjects
Biochemistry, Genetics and Molecular Biology (miscellaneous), Molecular Biology, Biochemistry
Abstract

Persistent sensory, motor and cognitive disabilities comprise chemotherapy-induced neural disorders (CIND) that limit quality of life with little therapeutic relief for cancer survivors. Our recent preclinical study provides new insight into a condition impacting the severity of chronic CIND. We find that sensorimotor disability observed following cancer treatment exceeds that attributable to chemotherapy alone. A possible explanation for intensified disability emerged from evidence that codependent effects of cancer and chemotherapy amplify defective firing in primary sensory neurons supplying one type of low threshold mechanosensory receptor (LTMR). Here we test whether cancer’s modification of chemotherapy-induced sensory defects generalizes across eight LTMR submodalities that collectively generate the signals of origin for proprioceptive and tactile perception and guidance of body movement. Preclinical study enabled controlled comparison of the independent contributions of chemotherapy and cancer to their clinically relevant combined effects. We compared data sampled from rats that were otherwise healthy or bearing colon cancer and treated, or not, with human-scaled, standard-of-care chemotherapy with oxaliplatin. Action potential firing patterns encoding naturalistic mechanical perturbations of skeletal muscle and skin were measured electrophysiologically in vivo from multiple types of LTMR neurons. All expressed aberrant encoding of dynamic and/or static features of mechanical stimuli in healthy rats treated with chemotherapy, and surprisingly also by some LTMRs in cancer-bearing rats that were not treated. By comparison, chemotherapy and cancer in combination worsened encoding aberrations, especially in slowly adapting LTMRs supplying both muscle and glabrous skin. Probabilistic modeling best predicted observed encoding defects when incorporating interaction effects of cancer and chemotherapy. We conclude that for multiple mechanosensory submodalities, the severity of encoding defects is modulated by a codependence of chemotherapy side effects and cancer’s systemic processes. We propose that the severity of CIND might be reduced by therapeutically targeting the mechanisms, yet to be determined, by which cancer magnifies chemotherapy’s neural side effects as an alternative to reducing chemotherapy and its life-saving benefits.

Published
2022

14. Structural preservation does not ensure function at sensory Ia – motoneuron synapses following peripheral nerve injury and repair

Author

Travis M. Rotterman, Violet V. García, Stephen N. Housley, Paul Nardelli, Rommy Sierra, Caitlin E. Fix, and Timothy C. Cope

Subjects
General Neuroscience
Abstract

Injury that severs peripheral nerves often results in long-lasting motor behavioral deficits and in reorganization of related spinal motor circuitry, neither of which reverse even after nerve regeneration. Stretch areflexia and gait ataxia, for example, emerges from a combination of factors including degeneration of Ia – motoneuron synapses between peripherally damaged Ia muscle spindle afferents and motoneurons. Based on evidence that nerve injury acts through immune responses to induce synapse degeneration, we hypothesized that suppressing inflammatory responses would preserve Ia – motoneuron connectivity and aid in restoring normal function. We tested our hypothesis by administering the anti-inflammatory agent minocycline in male and female rats following axotomy of a peripheral nerve. The connectivity of Ia – motoneuron synapses was then assessed both structurally and functionally at different time points. We found that minocycline treatment overcame the physical loss of Ia contacts on motoneurons which are otherwise lost after axotomy. While necessary for functional recovery, synaptic preservation was not sufficient to overcome functional decline expressed as smaller than normal stretch-evoked synaptic potentials (SSP) evoked monosynaptically at Ia – motoneuron connections and an absence of the stretch reflex. These findings demonstrate a limited capacity of minocycline to rescue normal sensorimotor behavior, illustrating that structural preservation of synaptic connectivity does not ensure normal synaptic function.Significance Statement:Here we demonstrate that acute treatment with the semisynthetic tetracycline anti-inflammatory agent minocycline permanently prevents the comprehensive loss of synaptic contacts made between sensory neurons and spinal motoneurons following peripheral nerve injury and eventual regeneration. Treatment failed, however, to rescue normal function of those synapses or the reflex circuit they mediate. These findings demonstrate that preventing synaptic disconnection alone is not sufficient to restore neural circuit operation and associated sensorimotor behaviors.

Published
2023
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15. Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice

Author

Navjot Pabla, Maryam B. Lustberg, Alix F. Leblanc, Kevin M. Huang, Eric D. Eisenmann, Mingqing Chen, Jing Wang, Yang Li, Jiyoung Kim, Sherry H. Xia, Timothy C. Cope, Muhammad Erfan Uddin, Charles L. Loprinzi, Kristen W. Hong, Alice A. Gibson, Alex Sparreboom, Paola Alberti, Alessia Chiorazzi, Stephen N. Housley, Anne M. Noonan, Shuiying Hu, Duncan DiGiacomo, Guido Cavaletti, Jason A. Sprowl, Huang, K, Leblanc, A, Uddin, M, Kim, J, Chen, M, Eisenmann, E, Gibson, A, Li, Y, Hong, K, Digiacomo, D, Xia, S, Alberti, P, Chiorazzi, A, Housley, S, Cope, T, Sprowl, J, Wang, J, Loprinzi, C, Noonan, A, Lustberg, M, Cavaletti, G, Pabla, N, Hu, S, and Sparreboom, A

Subjects
Male, 0301 basic medicine, Colorectal cancer, ved/biology.organism_classification_rank.species, Pharmacology, Oxaliplatin, neuropathy, neurotoxicity, OCT2, animal model, rodent model, neurophysiology, Neuroprotection, Mice, 03 medical and health sciences, 0302 clinical medicine, Animals, Medicine, Model organism, Mice, Knockout, Neurons, business.industry, ved/biology, Concise Communication, Neurotoxicity, Organic Cation Transporter 2, Cancer, Transporter, General Medicine, medicine.disease, Rats, Oxaliplatin, 030104 developmental biology, 030220 oncology & carcinogenesis, Genetically Engineered Mouse, Female, Neurotoxicity Syndromes, business, Neuroglia, medicine.drug
Abstract

Peripheral neurotoxicity is a debilitating toxicity that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically-engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells to oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventative strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.

Published
2020
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16. Cancer Exacerbates Chemotherapy-Induced Sensory Neuropathy

Author

Dario I. Carrasco, Paul Nardelli, John F. McDonald, Emily Pfahl, Timothy C. Cope, Stephen N. Housley, Lilya V. Matyunina, and Travis M. Rotterman

Subjects
Male, 0301 basic medicine, Cancer Research, Sensory Receptor Cells, medicine.medical_treatment, Antineoplastic Agents, Sensory system, Article, 03 medical and health sciences, 0302 clinical medicine, Chemotherapy induced, Biomarkers, Tumor, medicine, Animals, Differential expression, Chemotherapy, business.industry, Gene Expression Profiling, Peripheral Nervous System Diseases, medicine.disease, Rats, Inbred F344, Sensory neuron, Rats, Gene Expression Regulation, Neoplastic, Oxaliplatin, Disease Models, Animal, 030104 developmental biology, Peripheral neuropathy, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Sensory neuropathy, Forelimb, Colorectal Neoplasms, business, Neuroscience
Abstract

For the constellation of neurologic disorders known as chemotherapy-induced peripheral neuropathy, mechanistic understanding and treatment remain deficient. Here, we present the first evidence that chronic sensory neuropathy depends on nonlinear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism, and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as one potential contributor to sensory neuron dysfunction. Validated measures of sensorimotor behavior in awake, behaving animals revealed dysfunction after chronic chemotherapy treatment was exacerbated by cancer. Notably, errors in precise forelimb placement emerged as a novel behavioral deficit unpredicted by our previous study of chemotherapy alone. These original findings identify novel contributors to peripheral neuropathy and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer. Significance: These findings highlight the need to account for pathobiological interactions between cancer and chemotherapy as a major contributor to neuropathy and will have significant and immediate impact on future investigations in this field.

Published
2020
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17. Cancer survivors post-chemotherapy exhibit unique proprioceptive deficits in proximal limbs

Author

Allison B. Wang, Ann Marie Flores, Stephen N. Housley, Timothy C. Cope, and Eric J. Perreault

Subjects
Oncology, medicine.medical_specialty, Proprioception, business.industry, Rehabilitation, Cancer, Peripheral Nervous System Diseases, Health Informatics, medicine.disease, Upper Extremity, Cancer Survivors, Internal medicine, Neoplasms, Sensation Disorders, medicine, Humans, Post-chemotherapy, business
Abstract

Background Oxaliplatin (OX) chemotherapy for colorectal cancer is associated with adverse neurotoxic effects that can contribute to long-term sensorimotor impairments in cancer survivors. It is often thought that the sensorimotor impairments are dominated by OX-induced dying-back sensory neuropathy that primarily affects the distal regions of the limb. Recent preclinical studies have identified encoding dysfunction of muscle proprioceptors as an alternative mechanism. Unlike the dying-back sensory neuropathy affecting distal limbs, dysfunction of muscle proprioceptors could have more widespread effects. Most investigations of chemotherapy-induced sensorimotor impairments have considered only the effects of distal changes in sensory processing; none have evaluated proximal changes or their influence on function. Our study fills this gap by evaluating the functional use of proprioception in the shoulder and elbow joints of cancer survivors post OX chemotherapy. We implemented three multidirectional sensorimotor tasks: force matching, target reaching, and postural stability tasks to evaluate various aspects of proprioception and their use. Force and kinematic data of the sensorimotor tasks were collected in 13 cancer survivors treated with OX and 13 age-matched healthy controls. Results Cancer survivors exhibited less accuracy and precision than an age-matched control group when they had to rely only on proprioceptive information to match force, even for forces that required only torques about the shoulder. There were also small differences in the ability to maintain arm posture but no significant differences in reaching. The force deficits in cancer survivors were significantly correlated with self-reported motor dysfunction. Conclusions These results suggest that cancer survivors post OX chemotherapy exhibit proximal proprioceptive deficits, and that the deficits in producing accurate and precise forces are larger than those for producing unloaded movements. Current clinical assessments of chemotherapy-related sensorimotor dysfunction are largely limited to distal symptoms. Our study suggests that we also need to consider changes in proximal function. Force matching tasks similar to those used here could provide a clinically meaningful approach to quantifying OX-related movement dysfunction during and after chemotherapy.

Published
2022
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18. Cardiac troponins and adverse outcomes in European patients with atrial fibrillation: A report from the ESC-EHRA EORP atrial fibrillation general long-term registry

Author

Marco Vitolo, Vincenzo L. Malavasi, Marco Proietti, Igor Diemberger, Laurent Fauchier, Francisco Marin, Michael Nabauer, Tatjana S. Potpara, Gheorghe-Andrei Dan, Zbigniew Kalarus, Luigi Tavazzi, Aldo Pietro Maggioni, Deirdre A. Lane, Gregory Y.H. Lip, Giuseppe Boriani, G. Boriani, G.Y.H. Lip, L. Tavazzi, A.P. Maggioni, G-A. Dan, T. Potpara, M. Nabauer, F. Marin, Z. Kalarus, L. Fauchier, A. Goda, G. Mairesse, T. Shalganov, L. Antoniades, M. Taborsky, S. Riahi, P. Muda, I. García Bolao, O. Piot, K. Etsadashvili, M. Haim, A. Azhari, J. Najafian, M. Santini, E. Mirrakhimov, K. Kulzida, A. Erglis, L. Poposka, M.R. Burg, H. Crijns, Ö. Erküner, D. Atar, R. Lenarczyk, M. Martins Oliveira, D. Shah, E. Serdechnaya, E. Diker, E. Zëra, U. Ekmekçiu, V. Paparisto, M. Tase, H. Gjergo, J. Dragoti, M. Ciutea, N. Ahadi, Z. el Husseini, M. Raepers, J. Leroy, P. Haushan, A. Jourdan, C. Lepiece, L. Desteghe, J. Vijgen, P. Koopman, G. Van Genechten, H. Heidbuchel, T. Boussy, M. De Coninck, H. Van Eeckhoutte, N. Bouckaert, A. Friart, J. Boreux, C. Arend, P. Evrard, L. Stefan, E. Hoffer, J. Herzet, M. Massoz, C. Celentano, M. Sprynger, L. Pierard, P. Melon, B. Van Hauwaert, C. Kuppens, D. Faes, D. Van Lier, A. Van Dorpe, A. Gerardy, O. Deceuninck, O. Xhaet, F. Dormal, E. Ballant, D. Blommaert, D. Yakova, M. Hristov, T. Yncheva, N. Stancheva, S. Tisheva, M. Tokmakova, F. Nikolov, D. Gencheva, B. Kunev, M. Stoyanov, D. Marchov, V. Gelev, V. Traykov, A. Kisheva, H. Tsvyatkov, R. Shtereva, S. Bakalska-Georgieva, S. Slavcheva, Y. Yotov, M. Kubíčková, A. Marni Joensen, A. Gammelmark, L. Hvilsted Rasmussen, P. Dinesen, S. Krogh Venø, B. Sorensen, A. Korsgaard, K. Andersen, C. Fragtrup Hellum, A. Svenningsen, O. Nyvad, P. Wiggers, O. May, A. Aarup, B. Graversen, L. Jensen, M. Andersen, M. Svejgaard, S. Vester, S. Hansen, V. Lynggaard, M. Ciudad, R. Vettus, A. Maestre, S. Castaño, S. Cheggour, J. Poulard, V. Mouquet, S. Leparrée, J. Bouet, J. Taieb, A. Doucy, H. Duquenne, A. Furber, J. Dupuis, J. Rautureau, M. Font, P. Damiano, M. Lacrimini, J. Abalea, S. Boismal, T. Menez, J. Mansourati, G. Range, H. Gorka, C. Laure, C. Vassalière, N. Elbaz, N. Lellouche, K. Djouadi, F. Roubille, D. Dietz, J. Davy, M. Granier, P. Winum, C. Leperchois-Jacquey, H. Kassim, E. Marijon, J. Le Heuzey, J. Fedida, C. Maupain, C. Himbert, E. Gandjbakhch, F. Hidden-Lucet, G. Duthoit, N. Badenco, T. Chastre, X. Waintraub, M. Oudihat, J. Lacoste, C. Stephan, H. Bader, N. Delarche, L. Giry, D. Arnaud, C. Lopez, F. Boury, I. Brunello, M. Lefèvre, R. Mingam, M. Haissaguerre, M. Le Bidan, D. Pavin, V. Le Moal, C. Leclercq, T. Beitar, I. Martel, A. Schmid, N. Sadki, C. Romeyer-Bouchard, A. Da Costa, I. Arnault, M. Boyer, C. Piat, N. Lozance, S. Nastevska, A. Doneva, B. Fortomaroska Milevska, B. Sheshoski, K. Petroska, N. Taneska, N. Bakrecheski, K. Lazarovska, S. Jovevska, V. Ristovski, A. Antovski, E. Lazarova, I. Kotlar, J. Taleski, S. Kedev, N. Zlatanovik, S. Jordanova, T. Bajraktarova Proseva, S. Doncovska, D. Maisuradze, A. Esakia, E. Sagirashvili, K. Lartsuliani, N. Natelashvili, N. Gumberidze, R. Gvenetadze, N. Gotonelia, N. Kuridze, G. Papiashvili, I. Menabde, S. Glöggler, A. Napp, C. Lebherz, H. Romero, K. Schmitz, M. Berger, M. Zink, S. Köster, J. Sachse, E. Vonderhagen, G. Soiron, K. Mischke, R. Reith, M. Schneider, W. Rieker, D. Boscher, A. Taschareck, A. Beer, D. Oster, O. Ritter, J. Adamczewski, S. Walter, A. Frommhold, E. Luckner, J. Richter, M. Schellner, S. Landgraf, S. Bartholome, R. Naumann, J. Schoeler, D. Westermeier, F. William, K. Wilhelm, M. Maerkl, R. Oekinghaus, M. Denart, M. Kriete, U. Tebbe, T. Scheibner, M. Gruber, A. Gerlach, C. Beckendorf, L. Anneken, M. Arnold, S. Lengerer, Z. Bal, C. Uecker, H. Förtsch, S. Fechner, V. Mages, E. Martens, H. Methe, T. Schmidt, B. Schaeffer, B. Hoffmann, J. Moser, K. Heitmann, S. Willems, C. Klaus, I. Lange, M. Durak, E. Esen, F. Mibach, H. Mibach, A. Utech, M. Gabelmann, R. Stumm, V. Ländle, C. Gartner, C. Goerg, N. Kaul, S. Messer, D. Burkhardt, C. Sander, R. Orthen, S. Kaes, A. Baumer, F. Dodos, A. Barth, G. Schaeffer, J. Gaertner, J. Winkler, A. Fahrig, J. Aring, I. Wenzel, S. Steiner, A. Kliesch, E. Kratz, K. Winter, P. Schneider, A. Haag, I. Mutscher, R. Bosch, J. Taggeselle, S. Meixner, A. Schnabel, A. Shamalla, H. Hötz, A. Korinth, C. Rheinert, G. Mehltretter, B. Schön, N. Schön, A. Starflinger, E. Englmann, G. Baytok, T. Laschinger, G. Ritscher, A. Gerth, D. Dechering, L. Eckardt, M. Kuhlmann, N. Proskynitopoulos, J. Brunn, K. Foth, C. Axthelm, H. Hohensee, K. Eberhard, S. Turbanisch, N. Hassler, A. Koestler, G. Stenzel, D. Kschiwan, M. Schwefer, S. Neiner, S. Hettwer, M. Haeussler-Schuchardt, R. Degenhardt, S. Sennhenn, M. Brendel, A. Stoehr, W. Widjaja, S. Loehndorf, A. Logemann, J. Hoskamp, J. Grundt, M. Block, R. Ulrych, A. Reithmeier, V. Panagopoulos, C. Martignani, D. Bernucci, E. Fantecchi, I. Diemberger, M. Ziacchi, M. Biffi, P. Cimaglia, J. Frisoni, I. Giannini, S. Boni, S. Fumagalli, S. Pupo, A. Di Chiara, P. Mirone, F. Pesce, C. Zoccali, V.L. Malavasi, A. Mussagaliyeva, B. Ahyt, Z. Salihova, K. Koshum-Bayeva, A. Kerimkulova, A. Bairamukova, B. Lurina, R. Zuzans, S. Jegere, I. Mintale, K. Kupics, K. Jubele, O. Kalejs, K. Vanhear, M. Burg, M. Cachia, E. Abela, S. Warwicker, T. Tabone, R. Xuereb, D. Asanovic, D. Drakalovic, M. Vukmirovic, N. Pavlovic, L. Music, N. Bulatovic, A. Boskovic, H. Uiterwaal, N. Bijsterveld, J. De Groot, J. Neefs, N. van den Berg, F. Piersma, A. Wilde, V. Hagens, J. Van Es, J. Van Opstal, B. Van Rennes, H. Verheij, W. Breukers, G. Tjeerdsma, R. Nijmeijer, D. Wegink, R. Binnema, S. Said, S. Philippens, W. van Doorn, T. Szili-Torok, R. Bhagwandien, P. Janse, A. Muskens, M. van Eck, R. Gevers, N. van der Ven, A. Duygun, B. Rahel, J. Meeder, A. Vold, C. Holst Hansen, I. Engset, B. Dyduch-Fejklowicz, E. Koba, M. Cichocka, A. Sokal, A. Kubicius, E. Pruchniewicz, A. Kowalik-Sztylc, W. Czapla, I. Mróz, M. Kozlowski, T. Pawlowski, M. Tendera, A. Winiarska-Filipek, A. Fidyk, A. Slowikowski, M. Haberka, M. Lachor-Broda, M. Biedron, Z. Gasior, M. Kołodziej, M. Janion, I. Gorczyca-Michta, B. Wozakowska-Kaplon, M. Stasiak, P. Jakubowski, T. Ciurus, J. Drozdz, M. Simiera, P. Zajac, T. Wcislo, P. Zycinski, J. Kasprzak, A. Olejnik, E. Harc-Dyl, J. Miarka, M. Pasieka, M. Ziemińska-Łuć, W. Bujak, A. Śliwiński, A. Grech, J. Morka, K. Petrykowska, M. Prasał, G. Hordyński, P. Feusette, P. Lipski, A. Wester, W. Streb, J. Romanek, P. Woźniak, M. Chlebuś, P. Szafarz, W. Stanik, M. Zakrzewski, J. Kaźmierczak, A. Przybylska, E. Skorek, H. Błaszczyk, M. Stępień, S. Szabowski, W. Krysiak, M. Szymańska, J. Karasiński, J. Blicharz, M. Skura, K. Hałas, L. Michalczyk, Z. Orski, K. Krzyżanowski, A. Skrobowski, L. Zieliński, M. Tomaszewska-Kiecana, M. Dłużniewski, M. Kiliszek, M. Peller, M. Budnik, P. Balsam, G. Opolski, A. Tymińska, K. Ozierański, A. Wancerz, A. Borowiec, E. Majos, R. Dabrowski, H. Szwed, A. Musialik-Lydka, A. Leopold-Jadczyk, E. Jedrzejczyk-Patej, M. Koziel, M. Mazurek, K. Krzemien-Wolska, P. Starosta, E. Nowalany-Kozielska, A. Orzechowska, M. Szpot, M. Staszel, S. Almeida, H. Pereira, L. Brandão Alves, R. Miranda, L. Ribeiro, F. Costa, F. Morgado, P. Carmo, P. Galvao Santos, R. Bernardo, P. Adragão, G. Ferreira da Silva, M. Peres, M. Alves, M. Leal, A. Cordeiro, P. Magalhães, P. Fontes, S. Leão, A. Delgado, A. Costa, B. Marmelo, B. Rodrigues, D. Moreira, J. Santos, L. Santos, A. Terchet, D. Darabantiu, S. Mercea, V. Turcin Halka, A. Pop Moldovan, A. Gabor, B. Doka, G. Catanescu, H. Rus, L. Oboroceanu, E. Bobescu, R. Popescu, A. Dan, A. Buzea, I. Daha, G. Dan, I. Neuhoff, M. Baluta, R. Ploesteanu, N. Dumitrache, M. Vintila, A. Daraban, C. Japie, E. Badila, H. Tewelde, M. Hostiuc, S. Frunza, E. Tintea, D. Bartos, A. Ciobanu, I. Popescu, N. Toma, C. Gherghinescu, D. Cretu, N. Patrascu, C. Stoicescu, C. Udroiu, G. Bicescu, V. Vintila, D. Vinereanu, M. Cinteza, R. Rimbas, M. Grecu, A. Cozma, F. Boros, M. Ille, O. Tica, R. Tor, A. Corina, A. Jeewooth, B. Maria, C. Georgiana, C. Natalia, D. Alin, D. Dinu-Andrei, M. Livia, R. Daniela, R. Larisa, S. Umaar, T. Tamara, M. Ioachim Popescu, D. Nistor, I. Sus, O. Coborosanu, N. Alina-Ramona, R. Dan, L. Petrescu, G. Ionescu, C. Vacarescu, E. Goanta, M. Mangea, A. Ionac, C. Mornos, D. Cozma, S. Pescariu, E. Solodovnicova, I. Soldatova, J. Shutova, L. Tjuleneva, T. Zubova, V. Uskov, D. Obukhov, G. Rusanova, N. Isakova, S. Odinsova, T. Arhipova, E. Kazakevich, O. Zavyalova, T. Novikova, I. Riabaia, S. Zhigalov, E. Drozdova, I. Luchkina, Y. Monogarova, D. Hegya, L. Rodionova, V. Nevzorova, O. Lusanova, A. Arandjelovic, D. Toncev, L. Vukmirovic, M. Radisavljevic, M. Milanov, N. Sekularac, M. Zdravkovic, S. Hinic, S. Dimkovic, T. Acimovic, J. Saric, S. Radovanovic, A. Kocijancic, B. Obrenovic-Kircanski, D. Kalimanovska Ostric, D. Simic, I. Jovanovic, I. Petrovic, M. Polovina, M. Vukicevic, M. Tomasevic, N. Mujovic, N. Radivojevic, O. Petrovic, S. Aleksandric, V. Kovacevic, Z. Mijatovic, B. Ivanovic, M. Tesic, A. Ristic, B. Vujisic-Tesic, M. Nedeljkovic, A. Karadzic, A. Uscumlic, M. Prodanovic, M. Zlatar, M. Asanin, B. Bisenic, V. Vasic, Z. Popovic, D. Djikic, M. Sipic, V. Peric, B. Dejanovic, N. Milosevic, S. Backovic, A. Stevanovic, A. Andric, B. Pencic, M. Pavlovic-Kleut, V. Celic, M. Pavlovic, M. Petrovic, M. Vuleta, N. Petrovic, S. Simovic, Z. Savovic, S. Milanov, G. Davidovic, V. Iric-Cupic, D. Djordjevic, M. Damjanovic, S. Zdravkovic, V. Topic, D. Stanojevic, M. Randjelovic, R. Jankovic-Tomasevic, V. Atanaskovic, S. Antic, D. Simonovic, M. Stojanovic, S. Stojanovic, V. Mitic, V. Ilic, D. Petrovic, M. Deljanin Ilic, S. Ilic, V. Stoickov, S. Markovic, A. Mijatovic, D. Tanasic, G. Radakovic, J. Peranovic, N. Panic-Jelic, O. Vujadinovic, P. Pajic, S. Bekic, S. Kovacevic, A. García Fernandez, A. Perez Cabeza, M. Anguita, L. Tercedor Sanchez, E. Mau, J. Loayssa, M. Ayarra, M. Carpintero, I. Roldán Rabadan, M. Gil Ortega, A. Tello Montoliu, E. Orenes Piñero, S. Manzano Fernández, F. Marín, A. Romero Aniorte, A. Veliz Martínez, M. Quintana Giner, G. Ballesteros, M. Palacio, O. Alcalde, I. García-Bolao, V. Bertomeu Gonzalez, F. Otero-Raviña, J. García Seara, J. Gonzalez Juanatey, N. Dayal, P. Maziarski, P. Gentil-Baron, M. Koç, E. Onrat, I.E. Dural, K. Yilmaz, B. Özin, S. Tan Kurklu, Y. Atmaca, U. Canpolat, L. Tokgozoglu, A.K. Dolu, B. Demirtas, D. Sahin, O. Ozcan Celebi, G. Gagirci, U.O. Turk, H. Ari, N. Polat, N. Toprak, M. Sucu, O. Akin Serdar, A. Taha Alper, A. Kepez, Y. Yuksel, A. Uzunselvi, S. Yuksel, M. Sahin, O. Kayapinar, T. Ozcan, H. Kaya, M.B. Yilmaz, M. Kutlu, M. Demir, C. Gibbs, S. Kaminskiene, M. Bryce, A. Skinner, G. Belcher, J. Hunt, L. Stancombe, B. Holbrook, C. Peters, S. Tettersell, A. Shantsila, D. Lane, K. Senoo, M. Proietti, K. Russell, P. Domingos, S. Hussain, J. Partridge, R. Haynes, S. Bahadur, R. Brown, S. McMahon, J. McDonald, K. Balachandran, R. Singh, S. Garg, H. Desai, K. Davies, W. Goddard, G. Galasko, I. Rahman, Y. Chua, O. Payne, S. Preston, O. Brennan, L. Pedley, C. Whiteside, C. Dickinson, J. Brown, K. Jones, L. Benham, R. Brady, L. Buchanan, A. Ashton, H. Crowther, H. Fairlamb, S. Thornthwaite, C. Relph, A. McSkeane, U. Poultney, N. Kelsall, P. Rice, T. Wilson, M. Wrigley, R. Kaba, T. Patel, E. Young, J. Law, C. Runnett, H. Thomas, H. McKie, J. Fuller, S. Pick, A. Sharp, A. Hunt, K. Thorpe, C. Hardman, E. Cusack, L. Adams, M. Hough, S. Keenan, A. Bowring, J. Watts, J. Zaman, K. Goffin, H. Nutt, Y. Beerachee, J. Featherstone, C. Mills, J. Pearson, L. Stephenson, S. Grant, A. Wilson, C. Hawksworth, I. Alam, M. Robinson, S. Ryan, R. Egdell, E. Gibson, M. Holland, D. Leonard, B. Mishra, S. Ahmad, H. Randall, J. Hill, L. Reid, M. George, S. McKinley, L. Brockway, W. Milligan, J. Sobolewska, J. Muir, L. Tuckis, L. Winstanley, P. Jacob, S. Kaye, L. Morby, A. Jan, T. Sewell, C. Boos, B. Wadams, C. Cope, P. Jefferey, N. Andrews, A. Getty, A. Suttling, C. Turner, K. Hudson, R. Austin, S. Howe, R. Iqbal, N. Gandhi, K. Brophy, P. Mirza, E. Willard, S. Collins, N. Ndlovu, E. Subkovas, V. Karthikeyan, L. Waggett, A. Wood, A. Bolger, J. Stockport, L. Evans, E. Harman, J. Starling, L. Williams, V. Saul, M. Sinha, L. Bell, S. Tudgay, S. Kemp, L. Frost, T. Ingram, A. Loughlin, C. Adams, M. Adams, F. Hurford, C. Owen, C. Miller, D. Donaldson, H. Tivenan, H. Button, A. Nasser, O. Jhagra, B. Stidolph, C. Brown, C. Livingstone, M. Duffy, P. Madgwick, P. Roberts, E. Greenwood, L. Fletcher, M. Beveridge, S. Earles, D. McKenzie, D. Beacock, M. Dayer, M. Seddon, D. Greenwell, F. Luxton, F. Venn, H. Mills, J. Rewbury, K. James, K. Roberts, L. Tonks, D. Felmeden, W. Taggu, A. Summerhayes, D. Hughes, J. Sutton, L. Felmeden, M. Khan, E. Walker, L. Norris, L. O'Donohoe, A. Mozid, H. Dymond, H. Lloyd-Jones, G. Saunders, D. Simmons, D. Coles, D. Cotterill, S. Beech, S. Kidd, B. Wrigley, S. Petkar, A. Smallwood, R. Jones, E. Radford, S. Milgate, S. Metherell, V. Cottam, C. Buckley, A. Broadley, D. Wood, J. Allison, K. Rennie, L. Balian, L. Howard, L. Pippard, S. Board, and T. Pitt-Kerby

Subjects
Male, AF registry, Atrial fibrillation, Biomarkers, Death, Major adverse cardiovascular events, outcomes, Troponins, Troponin, Risk Factors, Atrial Fibrillation, Internal Medicine, Humans, Female, Prospective Studies, Registries, Aged
Abstract

BACKGROUND: Cardiac troponins (cTn) have been reported to be predictors for adverse outcomes in atrial fibrillation (AF), patients, but their actual use is still unclear.AIM: To assess the factors associated with cTn testing in routine practice and evaluate the association with outcomes.METHODS: Patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry were stratified into 3 groups according to cTn levels as (i) cTn not tested, (ii) cTn in range (≤99th percentile), (iii) cTn elevated (>99th percentile). The composite outcome of any thromboembolism /any acute coronary syndrome/cardiovascular (CV) death, defined as Major Adverse Cardiovascular Events (MACE) and all-cause death were the main endpoints.RESULTS: Among 10 445 AF patients (median age 71 years, 40.3% females) cTn were tested in 2834 (27.1%). cTn was elevated in 904/2834 (31.9%) and in-range in 1930/2834 (68.1%) patients. Female sex, in-hospital enrollment, first-detected AF, CV risk factors, history of coronary artery disease, and atypical AF symptoms were independently associated with cTn testing. Elevated cTn were independently associated with a higher risk for MACE (Model 1, hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.40-2.16, Model 2, HR 1.62, 95% CI 1.28-2.05; Model 3 HR 1.76, 95% CI 1.37-2.26) and all-cause death (Model 1, HR 1.45, 95% CI 1.21-1.74; Model 2, HR 1.36, 95% CI 1.12-1.66; Model 3, HR 1.38, 95% CI 1.12-1.71).CONCLUSIONS: Elevated cTn levels were associated with an increased risk of all-cause mortality and adverse CV events. Clinical factors that might enhance the need to rule out CAD were associated with cTn testing.

Published
2022
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19. Axon initial segment geometry in relation to motoneuron excitability

Author

Randall K. Powers, Paul Nardelli, Dario I. Carrasco, Travis M. Rotterman, Timothy C. Cope, and Stephen N. Housley

Subjects
Male, Muscle Physiology, Physiology, Neural Conduction, Action Potentials, Geometry, Nervous System, Nerve Fibers, Animal Cells, Medicine and Health Sciences, Biomechanics, Action potential initiation, Neurons, Motor Neurons, Multidisciplinary, musculoskeletal, neural, and ocular physiology, Physics, Muscles, musculoskeletal system, Electrophysiology, Rheobase, medicine.anatomical_structure, Spinal Cord, Physical Sciences, Medicine, Cellular Types, Anatomy, tissues, Research Article, Muscle Contraction, Science, Biophysics, Alpha (ethology), Neurophysiology, Biology, Membrane Potential, Neurons, Efferent, medicine, Animals, Rats, Wistar, Axon Initial Segment, Causal relations, Biology and Life Sciences, Motor pool, Cell Biology, Spinal cord, Axon initial segment, Axons, Rats, Neuroanatomy, nervous system, Cellular Neuroscience, Soma, Musculoskeletal Mechanics, Mathematics, Neuroscience
Abstract

The axon initial segment (AIS) responsible for action potential initiation is a dynamic structure that varies and changes together with neuronal excitability. Like other neuron types, alpha motoneurons in the mammalian spinal cord express heterogeneity and plasticity in AIS geometry, including length (AISl) and distance from soma (AISd). The present study aimed to establish the relationship of AIS geometry with a measure of intrinsic excitability, rheobase current, that varies by 20-fold or more among normal motoneurons. We began by determining whether AIS length or distance differed for motoneurons in motor pools that exhibit different activity profiles. Motoneurons sampled from the medial gastrocnemius (MG) motor pool exhibited values for average AISd that were significantly greater than that for motoneurons from the soleus (SOL) motor pool, which is more readily recruited in low-level activities. Next, we tested whether AISd covaried with intrinsic excitability of individual motoneurons. In anesthetized rats, we measured rheobase current intracellularly from MG motoneurons in vivo before labeling them for immunohistochemical study of AIS structure. For 16 motoneurons sampled from the MG motor pool, this combinatory approach revealed that AISd, but not AISl, was significantly related to rheobase, as AIS tended to be located further from the soma on motoneurons that were less excitable. Although a causal relation with excitability seems unlikely, AISd falls among a constellation of properties related to the recruitability of motor units and their parent motoneurons.

Published
2021

20. Neural circuit mechanisms of sensorimotor disability in cancer treatment

Author

Stephen N. Housley, Paul Nardelli, Travis M. Rotterman, and Timothy C. Cope

Subjects
Male, Multidisciplinary, sensory encoding, Antineoplastic Agents, Biological Sciences, Proprioception, Rats, Inbred F344, cancer treatment, Spinal Cord, sensorimotor disability, Neoplasms, spinal circuits, Animals, Female, synaptic function, Mechanoreceptors, Gait Disorders, Neurologic, Neuroscience
Abstract

Significance Severe and persistent disability often undermines the life-saving benefits of cancer treatment. Pain and fatigue, together with sensory, motor, and cognitive disorders, are chief among the constellation of side effects that occur with the platinum-based anticancer agents used in a majority of cancer treatments worldwide. These disabilities remain clinically unmitigated and empirically unexplained as research concentrates on peripheral degeneration of sensory neurons while understating the possible involvement of neural processes within the central nervous system. The present findings demonstrate functional defects in the fundamental properties of information processing localized within the central nervous system. We conclude that long-lasting sensorimotor and possibly other disabilities induced by cancer treatment result from independent neural defects compounded across both peripheral and central nervous systems., Cancer survivors rank sensorimotor disability among the most distressing, long-term consequences of chemotherapy. Disorders in gait, balance, and skilled movements are commonly assigned to chemotoxic damage of peripheral sensory neurons without consideration of the deterministic role played by the neural circuits that translate sensory information into movement. This oversight precludes sufficient, mechanistic understanding and contributes to the absence of effective treatment for reversing chemotherapy-induced disability. We rectified this omission through the use of a combination of electrophysiology, behavior, and modeling to study the operation of a spinal sensorimotor circuit in vivo in a rat model of chronic, oxaliplatin (chemotherapy)–induced neuropathy (cOIN). Key sequential events were studied in the encoding of propriosensory information and its circuit translation into the synaptic potentials produced in motoneurons. In cOIN rats, multiple classes of propriosensory neurons expressed defective firing that reduced accurate sensory representation of muscle mechanical responses to stretch. Accuracy degraded further in the translation of propriosensory signals into synaptic potentials as a result of defective mechanisms residing inside the spinal cord. These sequential, peripheral, and central defects compounded to drive the sensorimotor circuit into a functional collapse that was consequential in predicting the significant errors in propriosensory-guided movement behaviors demonstrated here in our rat model and reported for people with cOIN. We conclude that sensorimotor disability induced by cancer treatment emerges from the joint expression of independent defects occurring in both peripheral and central elements of sensorimotor circuits.

Published
2021

21. Modelling direct and herd protection effects of vaccination against the SARS-CoV-2 Delta variant in Australia

Author

Robert C. Cope, Emma S. McBryde, Romain Ragonnet, Samson T. Ogunlade, Pavithra Jayasundara, Jamie M Caldwell, Michael T. Meehan, Adeshina I. Adekunle, James M. Trauer, and Abdul Kuddus

Subjects
Adult, Immunity, Herd, COVID-19 Vaccines, Vaccination Coverage, Coronavirus disease 2019 (COVID-19), Adolescent, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Population, Mass Vaccination, Research and Reviews, Young Adult, Immunogenicity, Vaccine, COVID‐19, Medicine, Humans, Computer Simulation, education, Child, Epidemics, Health policy, BNT162 Vaccine, Health Services Administration, Vaccine preventable disease, education.field_of_study, business.industry, SARS-CoV-2, Research, Statistics, Epidemiologic measurements, Age Factors, Australia, Models, Immunological, COVID-19, General Medicine, Middle Aged, Vaccination, Epidemiology and Research Design, Years of potential life lost, Infectious Diseases, Vaccination coverage, Child, Preschool, Nonlinear dynamics, Herd, Environment and Public Health, business, Demography, Research Article
Abstract

Objectives To analyse the outcomes of COVID-19 vaccination by vaccine type, age group eligibility, vaccination strategy, and population coverage. Design Epidemiologic modelling to assess the final size of a COVID-19 epidemic in Australia, with vaccination program (Pfizer, AstraZeneca, mixed), vaccination strategy (vulnerable first, transmitters first, untargeted), age group eligibility threshold (5 or 15 years), population coverage, and pre-vaccination effective reproduction number ( R eff v ¯ ) for the SARS-CoV-2 Delta variant as factors. Main outcome measures Numbers of SARS-CoV-2 infections; cumulative hospitalisations, deaths, and years of life lost. Results Assuming R eff v ¯ = 5, the current mixed vaccination program (vaccinating people aged 60 or more with the AstraZeneca vaccine and people under 60 with the Pfizer vaccine) will not achieve herd protection unless population vaccination coverage reaches 85% by lowering the vaccination eligibility age to 5 years. At R eff v ¯ = 3, the mixed program could achieve herd protection at 60-70% population coverage and without vaccinating 5-15-year-old children. At R eff v ¯ = 7, herd protection is unlikely to be achieved with currently available vaccines, but they would still reduce the number of COVID-19-related deaths by 85%. Conclusion Vaccinating vulnerable people first is the optimal policy when population vaccination coverage is low, but vaccinating more socially active people becomes more important as the R eff v ¯ declines and vaccination coverage increases. Assuming the most plausible R eff v ¯ of 5, vaccinating more than 85% of the population, including children, would be needed to achieve herd protection. Even without herd protection, vaccines are highly effective in reducing the number of deaths.

Published
2021

22. Vaccination is Australia's most important COVID-19 public health action, even though herd immunity is unlikely

Author

Michael T. Meehan, Samson T. Ogunlade, James M. Trauer, Abdul Kuddus, Emma S. McBryde, Romain Ragonnet, Adeshina I. Adekunle, Robert C. Cope, Jamie Sziklay, and Pavithra Jayasundara

Subjects
medicine.medical_specialty, education.field_of_study, Coronavirus disease 2019 (COVID-19), business.industry, animal diseases, Public health, Population, Severe disease, Herd immunity, Vaccination, Age groups, Herd, Medicine, business, education, Demography
Abstract

The Australian National Cabinet four-step plan to transition to post-pandemic re-opening begins with vaccination to achieve herd protection and protection of the health system against a surge in COVID-19 cases. Assuming a pre-vaccination reproduction number for the Delta variant of 5, we show that for the current Mixed program of vaccinating over 60s with AstraZeneca and 16-60s with Pfizer we would not achieve herd immunity. We would need to cover 85% of the population (including many 5-16 year-olds to achieve herd immunity). At lower reproduction number of 3 and our current Mixed strategy, we can achieve herd immunity without vaccinating 5-15 year olds. This will be achieved at a 60% coverage pursuing a strategy targetting high transmitters or 70% coverage using a strategy targetting the vulnerable first. A reproduction number of 7 precludes achieving herd immunity, however vaccination is able to prevent 75% of deaths compared with no vaccination. We also examine the impact of vaccination on death in the event that herd immunity is not achieved. Direct effects of vaccination on reducing death are very good for both Pfizer and AstraZeneca vaccines. However we estimate that the Mixed or Pfizer program performs better than the AstraZeneca program. Furthermore, vaccination levels below the herd immunity threshold can lead to substantial (albeit incomplete) indirect protection for both vaccinated and unvaccinated populations. Given the potential for not reaching herd immunity, we need to consider what level of severe disease and death is acceptable, balanced against the consequences of ongoing aggressive control strategies. O_TEXTBOXThe known: SARS CoV-2 variants are known to be more transmissible than the original Wuhan strain, making herd immunity challenging. The new: We find that vaccinating the older-vulnerable age groups first leads to fewer deaths and is the optimal strategy vaccine coverage is under 70%. Herd immunity achieved solely through vaccinating adults is unlikely, but can still be expected to prevent substantial numbers of deaths. The implications: Australia is unlikely to achieve herd immunity unless vaccination is combined with substantial public health measures. Even without herd immunity, vaccination remains a highly effective means to mitigate the impact of COVID-19. C_TEXTBOX

Published
2021
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23. Somatic Proximity of the Axon Initial Segment Predicts Motoneuron Excitability

Author

Randy K Powers, Travis M. Rotterman, Dario I. Carrasco, Paul Nardelli, Nick Housley, and Timothy C. Cope

Subjects
Text mining, business.industry, Somatic cell, Biology, business, Axon initial segment, Neuroscience
Abstract

As the neuronal site where voltage gated channel density is highest, the axon initial segment (AIS) plays a key role in establishing a neuron’s action potential threshold, i.e. excitability. Among the properties of AIS that gain attention are length (AISl) and distance from the soma (AISd), which are variously found to change together with neuronal excitability following experimentally-induced perturbations in neural activity. The present study was designed to test the possibility that variation in AIS structural parameters regulates the native range in intrinsic excitability for one class of mature neurons. Spinal motoneurons were selected for their naturally large range in excitability and for their experimental accessibility to in vivo study. We began by determining whether AIS length or distance differed for motoneurons in motor pools that exhibit different activity profiles. Motoneurons sampled from the medial gastrocnemius (MG) motor pool exhibited values for average AISd that were significantly more than for motoneurons from the soleus (SOL) motor pool, which is more readily activated in low-level movements. Next, we tested whether AISd covaried with intrinsic excitability of individual motoneurons. Using anesthetized rats, we measured rheobase current intracellularly from MG motoneurons before labeling them for later immunohistochemical study of AIS. This combinatory approach revealed a significant correlation between AISd and rheobase, for 16 motoneurons sampled within the MG motor pool. Among multiple electrophysiological and morphological parameters measured here, AISd stood out as the dominant predictor of motoneuron excitability. These findings suggest an important role for AISd in setting the intrinsic excitability of spinal motoneurons.

Published
2021
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24. Diverse and complex muscle spindle afferent firing properties emerge from multiscale muscle mechanics

Author

Kyle P. Blum, Stephen N. Housley, Timothy C. Cope, Lena H. Ting, Paul Nardelli, Brian C. Horslen, and Kenneth S. Campbell

Subjects
0301 basic medicine, biophysical model, QH301-705.5, Mammalian muscle, Movement, proprioception, Science, Muscle spindle, Sensory system, sensory coding, Models, Biological, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Afferent, medicine, Animals, Computer Simulation, Rats, Wistar, Biology (General), Muscle Spindles, Muscle force, Physics, General Immunology and Microbiology, Proprioception, General Neuroscience, Dynamics (mechanics), Muscle mechanics, General Medicine, Rats, 030104 developmental biology, medicine.anatomical_structure, Active muscle, Rat, Medicine, Female, Neuroscience, 030217 neurology & neurosurgery, Research Article, Computational and Systems Biology, Muscle Contraction
Abstract

Despite decades of research, we lack a mechanistic framework capable of predicting how movement-related signals are transformed into the diversity of muscle spindle afferent firing patterns observed experimentally, particularly in naturalistic behaviors. Here, a biophysical model demonstrates that well-known firing characteristics of muscle spindle Ia afferents – including dependence on movement history, and nonlinear scaling with muscle stretch velocity – emerge from first principles of muscle contractile mechanics. Further, mechanical interactions of the muscle spindle with muscle-tendon dynamics reveal how motor commands to the muscle (alpha drive) versus muscle spindle (gamma drive) can cause highly variable and complex activity during active muscle contraction and muscle stretch that defy simple explanation. Depending on the neuromechanical conditions, the muscle spindle model output appears to “encode” aspects of muscle force, yank, length, stiffness, velocity, and/or acceleration, providing an extendable, multiscale, biophysical framework for understanding and predicting proprioceptive sensory signals in health and disease.

Published
2020
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26. Synaptic Plasticity on Motoneurons After Axotomy: A Necessary Change in Paradigm

Author

Travis M. Rotterman, Erica T. Akhter, Arthur W. English, Alicia R. Lane, Francisco J. Alvarez, and Timothy C. Cope

Subjects
0301 basic medicine, medicine.medical_treatment, microglia, Sensory system, Review, Biology, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, sensorimotor integration, Axon, Molecular Biology, motoneuron, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, synaptic plasticity, Microglia, astrocytes, Spinal cord, axotomy, 030104 developmental biology, medicine.anatomical_structure, nervous system, regeneration, Ia afferent synapses, Synaptic plasticity, Axotomy, Neuroscience, 030217 neurology & neurosurgery, Astrocyte, Reinnervation
Abstract

Motoneurons axotomized by peripheral nerve injuries experience profound changes in their synaptic inputs that are associated with a neuroinflammatory response that includes local microglia and astrocytes. This reaction is conserved across different types of motoneurons, injuries, and species, but also displays many unique features in each particular case. These reactions have been amply studied, but there is still a lack of knowledge on their functional significance and mechanisms. In this review article, we compiled data from many different fields to generate a comprehensive conceptual framework to best interpret past data and spawn new hypotheses and research. We propose that synaptic plasticity around axotomized motoneurons should be divided into two distinct processes. First, a rapid cell-autonomous, microglia-independent shedding of synapses from motoneuron cell bodies and proximal dendrites that is reversible after muscle reinnervation. Second, a slower mechanism that is microglia-dependent and permanently alters spinal cord circuitry by fully eliminating from the ventral horn the axon collaterals of peripherally injured and regenerating sensory Ia afferent proprioceptors. This removes this input from cell bodies and throughout the dendritic tree of axotomized motoneurons as well as from many other spinal neurons, thus reconfiguring ventral horn motor circuitries to function after regeneration without direct sensory feedback from muscle. This process is modulated by injury severity, suggesting a correlation with poor regeneration specificity due to sensory and motor axons targeting errors in the periphery that likely render Ia afferent connectivity in the ventral horn nonadaptive. In contrast, reversible synaptic changes on the cell bodies occur only while motoneurons are regenerating. This cell-autonomous process displays unique features according to motoneuron type and modulation by local microglia and astrocytes and generally results in a transient reduction of fast synaptic activity that is probably replaced by embryonic-like slow GABA depolarizations, proposed to relate to regenerative mechanisms.

Published
2020
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27. Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study

Author

Kirmeier E. a, Eriksson L. I. c, Lewald H. a, Jonsson Fagerlund, M. c Hoeft, A. f Hollmann, M. g Meistelman, C. e Hunter, J. M. d Ulm, K. b Blobner, M. aEmail Author, Abad Gurumeta, A. Abernethy, C. Abigail, P. Achaibar, K. Adam, E. Afshari, Agudelo Montoya, M. E. Akgün, F. N. Aletti, G. Alkış, N. Allan, K. Allan, A. Allaouchiche, B. Allcock, C. Almasy, E. Amey, I. Amigoni, M. Andersen, E. Andersson, P. Anipchenko, N. Antunes, P. Armstrong, E. Aslam, T. N. Aslin, B. Assunção, J. P. Ausserer, J. Avvai, M. Awad, Ayas Montero, B. Ayuso, M. Azevedo, P. Badarau, V. Badescu, Baiardo Redaelli, M. Baird, C. Baird, Y. Baker, T. Balaji, P. Bălan, C. Balandin, A. Balescu-Arion, C. Baliuliene, Baltasar Isabel, J. Baluch, S. N. Bandrabur, D. Bankewitz, C. Barber, K. Barbera, F. Barcraft-Barnes, H. Barletti, V. Barnett, G. Baron, K. Barros, A. Barsan, V. Bartlett, P. Batistaki, C. Baumgarten, G. Baytas, V. Beauchamp, Becerra Cayetano, I. A. Bell, S. Bellandi, M. Belletti, Belmonte Cuenca, J. Benitez-Cano, A. Beretta, L. Berger, M. Bergmann, N. Bergmark, Bermudez Lopez, M. Bernotaite, M. Beurskens, C. Bidd, H. Bifulco, F. Bignami, E. Bilic, A. Bilskiene, D. Bischoff, P. Bishop, L. Bjonness, T. Blaylock, H. Blethyn, K. Blincoe, T. Blokhin, I. Blunt, N. Boer, C. Bois, G. Bonicolini, E. Booth, J. Borecka-Kedzierska, M. Borstnar, K. Borys, M. Boselli, E. Bouvet, L. Bouwman, A. Bowen, L. Bowrey, S. Boxall, L. Božić, T. Bradley, T. Branco, T. Brazzi, L. Brazzoni, M. Brear, T. Brogly, N. Brohi, F. Broms, J. Bubliauskas, A. Bucolo, G. E. Buerkle, H. Buggy, D. Buhre, W. Bukauskas, T. Butturini, F. Byttner, Cabrera Díaz, I. Calderon, A. Calhau, R. Callejo, A. Cammu, G. Campesato, M. Can, Ö. S. Candeias, M. Cantor, A. Carise, E. Carmona, C. Carreteiro, J. Carrieri, C. Carter, A. Casal, M. Casanova, I. Cascella, M. Casero, L. M. Casiraghi, G. M. Castelo-Branco, Castro Arranz, C. Cernea, D. D. Cervantes, J. Chandler, B. Charnock, R. Chatzimicali, A. Chinery, E. Chishti, A. Chondhury, P. Christie, E. Christodoudiles, G. Ciardo, S. Cimpeanu, L. Cindea, I. Cinnella, G. Clark, S. Clayton, M. Cocu, S. Collyer, T. Colvin, C. Cope, S. Copeta, F. Copotoiu, S. -M., Correia de Barros, F. Corso, R. M. Cortegiani, A. Costa, G. Cowton, A. Cox, N. Craig, J. Cricca, V. Cronin, J. Cunha, M. Cuomo, A. Curley, K. Czuczwar, M. Dabrowska, D. Damster, Danguy des Déserts, M. Daniliuc, A. Danninger, T. Darwish, I. Dascalu, C. Davies, K. Davies, De Boer, De Flaviis, De Selincourt, G. Deana, C. Debaene, B. Debreceni, G. Dedhia, Delgado Garcia, Della Rocca, G. Delroy-Buelles, L. Desai, T. Dhillon, Di Giacinto, Di Mauro, Diaz Gomez, T. V. Dimitrovski, A. Dinic, V. Dîrzu, D. -S., Divander M. B., Dolinar J., Domingues S., Doolan J., Downes C., Dragoescu N. A., Droc G., Dum E., Dumitrescu A., Duncan L., Dzurňáková P., Eberl S., Edwards J., Edwards M., Ekelund K., Ekengren P., Elghouty E., Ellerkmann R., Ellis H., Elme A., Ernst T., Errando C. L., Estenes S., Ewaldsson C., Farid N., Featherstone J., Febres D., Fedorov S., Feggeler J., Feijten P., Fellmann T., Fernandez Candil, Fernandez Castineira, Fernández Castineira, J. Fernando, A. Ferrando, C. Ferreira, L. Ferreira, P. Feyling, A. Filipescu, D. Fleischer, A. Floris, L. Foerster, U. Fox, B. Franke, U. Frasca, D. Frey, C. Frost, V. Fullin, G. Fumagalli, J. Furneval, J. Fusari, M. Gallacher, S. Galushka, S. Gambale, G. Gambino, I. Garcia-Perez, M. L. Garg, S. Garlak, J. Gavranovic, Z. Gavrilov, R. Gaynor, Gecaj Gashi, A. Georghiou, M. Gerjevic, B. Gferer, G. Giarratano, A. Gibson, A. Gievski, V. Giles, J. Gillberg, L. Gilowska, Gilsanz Rodriguez, F. Gioia, A. Giovannoni, C. Girotra, V. Gkinas, D. Gkiokas, G. Godoroja, D. Goebel, U. Goel, V. Gonzalez, M. Goranovic, T. Gornik-Wlaszczuk, E. Gosavi, S. Gottfridsson, P. Gottschalk, A. Granell, M. Granstrom, A. Grassetto, A. Greenwood, A. Grigoras, I. Grintescu, I. Gritsan, A. Gritsan, G. Grynyuk, A. Guadagnin, G. M. Guarnieri, M. Güçlü, Guerrero Diez, M. Gunenc, F. Günther, U. Gupta, P. Guttenthaler, V. Hack, Y. Hafisayena, A. Hagau, N. Haldar, J. Hales, D. Hancı, V. Hanna-Jumma, S. Harazim, H. Harlet, P. Harper, D. Harris, B. Harvey, O. Hashimi, M. Hawkins, L. Hayes, C. Heaton, J. Heier, T. Helliwell, L. Hemmes, S. Henderson, K. Hermanides, J. Hermanns, Herrera Hueso, B. Hestenes, S. Hettiarachchi, R. Highgate, J. Hodgson, K. Hoelbling, D. Holland, J. Horhota, L. Hormis, A. Hribar, R. Hua, A. Humphreys, S. Humphries, R. Humpliková, S. Hunt, J. Husnain, A. Hussein, A. Hyams, B. Iannuccelli, F. Ilette, K. Ilyas, C. Inan, T. India, I. Ionițăv, V. Irwin, F. Jain, V. Janez, B. Jankovic, R. Jenkins, S. Jenko, M. Jimenez, Jiménez Gomez, B. Joachim, S. Joelsson-Alm, E. John, J. Jonikaite, L. Jovic, M. Jungwirth, B. Junke, E. Kabakov, B. Kadaoui, S. -D., Kanski A., Karadag S., Karbonskiene A., Karjagin J., Kasnik D., Katanolli F., Katsika E., Kaufmann K., Keane H., Kelly M., Kent M., Keraitiene G., Khudhur A., Khuenl-Brady K., Kidd L., King S., Kirchgäßner K., Klancir T., Klucniks A., Knotzer J., Knowlden P., Koers L., Kompan J., Koneti K. K., Kooij F., Koolen E., Koopman - van Gemert, A. W. M. M. Kopp, K. Korfiotis, D. Korolkov, O. Kosinová, M. Köstenberger, M. Kotzinger, O. Kovačević, M. Kranke, P. Kranke, E. Kraus, C. Kraus, S. Kubitzek, C. Kucharski, R. Kucukguclu, S. Kudrashou, A. Kumar, V. Kummen, L. Kunit, C. Kushakovsky, V. Kuvaki, B. Kuzmanovska, B. Kyttari, A. Landoni, G. Lau, G. Lazarev, K. Legett, S. Legrottaglie, A. M. Leonardi, S. Leong, M. Lercher, H. Leuvrey, M. Leva, B. Levstek, M. Limb, J. Lindholm, E. Linton, F. Liperi, C. Lipski, F. Lirk, P. Lisi, A. Lišková, Lluch Oltra, A. Loganathan, V. Lombardi, S. Lopez, Lopez Rodríguez, M. Lorenzini, L. Lowicka, M. Lugovoy, A. Luippold, M. Lumb, A. Macas, A. Macgregor, M. Machado, H. Maciariello, M. Madeira, I. Maitan, S. Majewski, J. Maldini, B. Malewski, G. Manfredini, L. Männer, O. Marchand, B. Marcu, A. Margalef, J. Margarson, M. Marinheiro, L. Markic, Markovic Bozic, J. Marrazzo, F. Martin, Martin Ayuso, M. Martinez, E. Martino, E. A. Martinson, V. Marusic-Gaser, K. Mascarenhas, C. Mathis, C. Matsota, P. Mavrommati, Mazul Sunko, B. McCourt, K. McGill, N. McKee, R. Meço, B. C. Meier, S. Melbourne, S. Melbybråthen, G. Meli, A. Melia, A. Melotti, R. M. Menga, M. R. Mercer, P. Merotra, S. Mescolini, S. Metterlein, T. Michalov, M. Michlig, S. Midgley, S. Milić, M. Milojevic, M. Miñana, A. Minto, G. Mirabella, L. Mirea, L. Mittelstädt, L. Moeglen, A. Moise, A. Mokini, Z. Molin, A. Moltó, L. Monea, M. C. Montalto, F. Montgomery, J. Montgomery, C. Montillo, G. Moore, S. Moore, F. Moreira, Z. Moreno, T. Moreno, R. Moret, E. Moreton, S. Morgan, Moro Velasco, C. Morri, D. Moull, A. Moura, F. Mráz, P. Mrozek, K. Mukhtar, K. Muniyappa, S. Murray, H. Murthy, B. V. Mushambi, M. Nadolski, M. Nardelli, P. Nardin, Navarro Pérez, R. Naveiro, A. Negri, Nesek Adam, V. Neskovic, V. Neuwersch, S. Neves, M. Nguyen, Ní Eochagáin, A. Nicholas, C. Nightingale, J. Norrie, K. Novak-Jankovic, V. Novakova, A. Novillo, M. Numan, S. Oduro-Dominah, L. Oldner, A. Oliveira, I. Ologoiu, D. Oloktsidou, I. O'Reilly, R. Orlando, A. Ovezov, A. Ozbilgin, S. Paal, Padin Barreiro, L. Palugniok, R. Papaioannou, A. Papapostolou, K. Paranthaman, Pardey Bracho, G. Parente, S. Parfeni, A. Pasin, L. Passey, S. Pastor, E. Patch, S. Patil, A. Paunescu, M. -A., Pehboeck D., Pereira M., Pereira C., Perez Caballero, Pérez García, Pérez Soto, Perez Tejero, G. Perez-Cerda, F. Pesenti, A. Petta, R. Philippe, S. Pickering, Pico Veloso, J. Pina, P. Pinho-Oliveira, V. Pinol, S. Pinto, R. Pistidda, L. Pitterle, M. Piwowarczyk, P. Plotnikova, O. Pohl, H. Poldermann, J. Polkovicová, L. Pompei, L. Popescu, M. Popović, Pota V, Potocnik M., Potręć B., Potter A., Pramod N., Prchalova M., Preckel B., Pugh R., Pulletz M., Radoeshki A., Rafi A., Ragazzi R., Raineri Santi, M. Rajamanickam, T. Rajput, Z. Ramachandran, R. Ramasamy, R. Ramessur, S. Rao, R. Rasmussen, A. Rato, A. Razaque, Real Navacerrada, M. I. Reavley, C. Reid, J. Reschreiter, H. Rial, Ribas Carrasco, P. Ribeiro, S. Rich, N. Richardson, L. Rimaitis, K. Rimaitis, M. Ringvold, E. -M., Ripke F., Ristescu I., Ritchie K., Ródenas F., Rodrigues P., Rogers E., Rogerson D., Romagnoli S., Romero E., Rondovic G., Rose B. O., Roth W., Rotter, M. -T., Rousseau G., Rudjord A., Rueffert H., Rundgren M., Rupprecht K., Rushton A., Russotto V., Rypulak E., Ryszka M., Sà J., Sà Couto, P. Saby, S. Sagic, J. Saleh, O. Sales, Sánchez Sánchez, Y. Sanghera, Şanli Karip, Santiveri Papiol, F. J. Santos, S. Sarno, S. Saul, D. Saunders, D. Savic, N. Scalco, L. Scanlon, D. Schaller, S. Schax, C. Scheffer, G. J. Schening, A. Schiavone, V. Schmidt-Ehrenberg, F. 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Weber, Wegiel Leskiewiq, A. Weller, D. Wensing, C. Werkmann, M. Westberg, H. Wikström, E. Williams, B. Wilson, R. Wirth, S. Wittmann, M. Wood, L. Wright, S. Zachoval, C. Zambon, M. Zampieri, S. Zampone, S. Zangrillo, A. Zani, G. Zavackiene, A. Zieglerder, R. Zonneveldt, H. Zsisku, L. Zucker, T. -P., Żukowski M., Zuleika M., Zupanĕiĕ D., Kirmeier, E. a., Eriksson, L. I. c., Lewald, H. a., Jonsson, Fagerlund, Hoeft, M. c., Hollmann, A. f., Meistelman, M. g., Hunter, C. e., Ulm, J. M. d., Blobner, K. b., M., aEmail Author, Abad, Gurumeta, A., Abernethy, C., Abigail, P., Achaibar, K., Adam, E., Afshari, Agudelo, Montoya, M. E., Akgün, F. N., Aletti, G., Alkış, N., Allan, K., Allan, A., Allaouchiche, B., Allcock, C., Almasy, E., Amey, I., Amigoni, M., Andersen, E., Andersson, P., Anipchenko, N., Antune, P., Armstrong, E., Aslam, T. N., Aslin, B., Assunção, J. 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M., Leonardi, S., Leong, M., Lercher, H., Leuvrey, M., Leva, B., Levstek, M., Limb, J., Lindholm, E., Linton, F., Liperi, C., Lipski, F., Lirk, P., Lisi, A., Lišková, Lluch, Oltra, A., Loganathan, V., Lombardi, S., Lopez, Lopez, Rodríguez, M., Lorenzini, L., Lowicka, M., Lugovoy, A., Luippold, M., Lumb, A., Maca, A., Macgregor, M., Machado, H., Maciariello, M., Madeira, I., Maitan, S., Majewski, J., Maldini, B., Malewski, G., Manfredini, L., Männer, O., Marchand, B., Marcu, A., Margalef, J., Margarson, M., Marinheiro, L., Markic, Markovic, Bozic, J., Marrazzo, F., Martin, Martin, Ayuso, M., Martinez, E., Martino, E. A., Martinson, V., Marusic-Gaser, K., Mascarenha, C., Mathi, C., Matsota, P., Mavrommati, Mazul, Sunko, B., Mccourt, K., Mcgill, N., Mckee, R., Meço, B. C., Meier, S., Melbourne, S., Melbybråthen, G., Meli, A., Melia, A., Melotti, R. M., Menga, M. 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Suzana, Parfeni, Alexandru, Pasin, Laura, Passey, Samuel, Pastor, Ernesto, Patch, Sarah, Patil, Andan, Paunescu, Marilena-Alina, Pehboeck, Daniel, Pereira, Manuela, Pereira, Carla, Perez Caballero, Paula, Pérez García, Aníbal, Pérez Soto, Antonia, Perez Tejero, Gisela, Perez-Cerda, Francisco, Pesenti, Antonio, Petta, Rocco, Philippe, Simon, Pickering, David, Pico Veloso, Jandro, Pina, Pedro, Pinho-Oliveira, Vítor, Pinol, Santiago, Pinto, Rita, Pistidda, Laura, Pitterle, Manuela, Piwowarczyk, Paweł, Plotnikova, Olga, Pohl, Holger, Poldermann, Jorinde, Polkovicová, Lucia, Pompei, Livia, Popescu, Mihai, Popović, Radmila, Pota, Vincenzo, Potocnik, Miriam, Potręć, Beata, Potter, Alison, Pramod, Nalwaya, Prchalova, Martina, Preckel, Benedikt, Pugh, Richard, Pulletz, Mark, Radoeshki, Aleksandar, Rafi, Amir, Ragazzi, Riccardo, Raineri Santi, Maurizio, Rajamanickam, Tamiselvan, Rajput, Zahra, Ramachandran, Rajeskar, Ramasamy, Radhika, Ramessur, Suneil, Rao, Roshan, Rasmussen, Ander, Rato, André, Razaque, Usman, Real Navacerrada, M. Isabel, Reavley, Caroline, Reid, Jame, Reschreiter, Henrik, Rial, Erick, Ribas Carrasco, Patricia, Ribeiro, Sandy, Rich, Nathalie, Richardson, Lydia, Rimaitis, Kestuti, Rimaitis, Mariu, Ringvold, Else-Marie, Ripke, Fabian, Ristescu, Irina, Ritchie, Keith, Ródenas, Frederic, Rodrigues, Patrícia, Rogers, Emma, Rogerson, David, Romagnoli, Stefano, Romero, Esther, Rondovic, Goran, Rose, Bernd Oliver, Roth, Winfried, Rotter, Marie-Therese, Rousseau, Guy, Rudjord, Ander, Rueffert, Henrik, Rundgren, Malin, Rupprecht, Korbinian, Rushton, Andrew, Russotto, Vincenzo, Rypulak, Elżbieta, Ryszka, Maciej, Sà, Jacinta, Sà Couto, Paula, Saby, Sandrine, Sagic, Jelena, Saleh, Omar, Sales, Gabriele, Sánchez Sánchez, Yván, Sanghera, Sumayer, Şanli Karip, Ceren, Santiveri Papiol, Francisco Javier, Santos, Sofia, Sarno, Stephen, Saul, Daniel, Saunders, David, Savic, Nenad, Scalco, Loïc, Scanlon, Deborah, Schaller, Stefan, Schax, Christoph, Scheffer, Gert Jan, Schening, Anna, Schiavone, Vincenzo, Schmidt-Ehrenberg, Florian, Schmidt-Mutter, Catherine, Schönberg, Christina, Schopflin, Christian, Schreiber, Jan-Uwe, Schultz, Marcu, Schurig, Marlen, Scott, Carmen, Sebestian, Siby, Sehgal, Selena, Sem, Victoria, Semenas, Egidiju, Serafini, Elena, Serchan, Pashalitsa, Shields, Martin, Shobha, Ramakrishnan, Shosholcheva, Mirjana, Siamansour, Tanja, Siddaiah, Narendra, Siddiqi, Khalid, Sinclair, Rhona, Singh, Permendra, Singh, Rajendra, Sinha, Aneeta, Sinha, Ashok, Skinner, Amanda, Smee, Elizabeth, Smekalova, Olga, Smith, Neil, Smith, Thoma, Smitz, Carine, Smole, Daniel, Sojčić, Nataša, Soler Pedrola, Maria, Somanath, Sameer, Sonksen, Julian, Sorella, Maria Christina, Sörmus, Alar, Soro, Marina, Soto, Carmen, Spada, Anna, Spadaro, Savino, Spaeth, Johanne, Sparr, Harald, Spielmann, Annika, Spindler-Vesel, Alenka, Stamelos, Matthaio, Stancombe L, Liucia, Stanculescu, Andreea, Standl, Thoma, Standley, Tom, Stanek, Ondrej, Stanisavljević, Snežana, Starczewska, Malgorzata, Stäuble, Christiane, Steen, Julie, Stefan, Oana Maria, Stell, Elizabeth, Stera, Caterina, Stevens, Marku, Stoerckel, Marlène, Stošić, Biljana, Stourac, Petr, Stroumpoulis, Konstantino, Struck, Rafael, Suarez de la Rica, Alejandro, Sultanpori, Altaf, Sundara Rajan, Rajinikanth, Suying, Ong, Svensen, Christer, Swan, Louise, Syrogianni, Paulina, Sysiak, Justyna, Szederjesi, Jano, Taddei, Stefania, Tan Hao, Ern, Tanou, Virginia, Tarabová, Katarina, Tardaguila Sancho, Paula, Tarroso, Maria, Tartaglione, Marco, Taylor, Emma, Tbaily, Lee, Telford, Richard, Terenzoni, Massimo, Theodoraki, Kassiani, Thornley, Helen, Tiganiuc, Liviu, Toim, Hardo, Tomescu, Dana, Tommasino, Concezione, Toni, Jessica, Toninelli, Arturo, Toretti, Ilaria, Townley, Stephen, Trepenaitis, Dariu, Trethowan, Brian, Tsaousi, Georgia, Tsiftsi, Aikaterini, Tudor, Adrada, Turan, Güldem, Turhan, Sanem Çakar, Unic-Stojanovic, Dragana, Unterbuchner, Christoph, Unzueta, Carmen, Uranjek, Jasna, Ursic, Tomaz, Vaida, Simona, Valldeperas Ferrer, Silvia, Valldeperas Hernandez, Maria Inmaculada, Valsamidis, Dimitri, Van Beek, Rienk, Van dasselaer, Nick, Van Der Beek, Tim, Van Duivenvoorde, Yoni, van Klei, Wilton A., Van Poorter, Fran, Van Zaane, Ba, Van Zundert, Tom, Van Zyl, Rebekka, Vargas Munoz, Ana Milena, Varsani, Nimu, Vasconcelos, Pedro, Vassilakis, Georgio, Vecchiatini, Tommaso, Vecera, Lubomir, Vercauteren, Marcel, Verdouw, Ba, Verheyen, Veerle, Verri, Marco, Vicari Sottosanti, Luigi Giancarlo, Vico, Manuel, Vidal Mitjans, Patricia, Vilardi, Anna, Vissicchio, Daniela, Vitale, Giovanni, Vitković, Bibiana, Vizcaychipi, Marcela Paola, Voicu, Alexandra, Voje, Minca, Volfová, Ivana, Volta, Carlo Alberto, Von Lutterotti, Theresa, von Tiesenhausen, Anna, Vrecic-Slabe, Simona, Vukcevic, Dejan, Vukovic, Rade, Vullo, P. Agostina, Wade, Andrew, Wallberg, Hanna, Wallden, Jakob, Wallner, Johann, Walther Sturesson, Louise, Watson, Davina, Weber, Stefan, Wegiel Leskiewiq, Anna, Weller, Debbie, Wensing, Carine, Werkmann, Marku, Westberg, Henrik, Wikström, Erik, Williams, Benedict, Wilson, Robin, Wirth, Steffen, Wittmann, Maria, Wood, Laura, Wright, Stella, Zachoval, Christian, Zambon, Massimo, Zampieri, Silvia, Zampone, Salvatore, Zangrillo, Alberto, Zani, Gianluca, Zavackiene, Asta, Zieglerder, Raphael, Zonneveldt, Harry, Zsisku, Lajo, Zucker, Tom-Philipp, Żukowski, Maciej, Zuleika, Mehrun, and Zupanĕiĕ, Darja

Subjects
Pulmonary and Respiratory Medicine, pulmonary complications, muscle relaxants, Post-anaesthesia complications, Neuromuscular Blockade, pulmonary complication, muscle relaxant, neuromuscular block, postoperative pulmonary complication, business.industry, Retrospective cohort study, post-operative pulmonary complications, Neuromuscular monitoring, Neuromuscular Blocking Agents, Sugammadex, NO, Anaesthesia, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Anesthesia, Medicine, General anaesthesia, Neuromuscular Agents, 030212 general & internal medicine, MED/41 - ANESTESIOLOGIA, Prospective cohort study, business, medicine.drug
Abstract

Background: Results from retrospective studies suggest that use of neuromuscular blocking agents during general anaesthesia might be linked to postoperative pulmonary complications. We therefore aimed to assess whether the use of neuromuscular blocking agents is associated with postoperative pulmonary complications. Methods: We did a multicentre, prospective observational cohort study. Patients were recruited from 211 hospitals in 28 European countries. We included patients (aged ≥18 years) who received general anaesthesia for any in-hospital procedure except cardiac surgery. Patient characteristics, surgical and anaesthetic details, and chart review at discharge were prospectively collected over 2 weeks. Additionally, each patient underwent postoperative physical examination within 3 days of surgery to check for adverse pulmonary events. The study outcome was the incidence of postoperative pulmonary complications from the end of surgery up to postoperative day 28. Logistic regression analyses were adjusted for surgical factors and patients' preoperative physical status, providing adjusted odds ratios (ORadj) and adjusted absolute risk reduction (ARRadj). This study is registered with ClinicalTrials.gov, number NCT01865513. Findings: Between June 16, 2014, and April 29, 2015, data from 22 803 patients were collected. The use of neuromuscular blocking agents was associated with an increased incidence of postoperative pulmonary complications in patients who had undergone general anaesthesia (1658 [7·6%] of 21 694); ORadj 1·86, 95% CI 1·53–2·26; ARRadj −4·4%, 95% CI −5·5 to −3·2). Only 2·3% of high-risk surgical patients and those with adverse respiratory profiles were anaesthetised without neuromuscular blocking agents. The use of neuromuscular monitoring (ORadj 1·31, 95% CI 1·15–1·49; ARRadj −2·6%, 95% CI −3·9 to −1·4) and the administration of reversal agents (1·23, 1·07–1·41; −1·9%, −3·2 to −0·7) were not associated with a decreased risk of postoperative pulmonary complications. Neither the choice of sugammadex instead of neostigmine for reversal (ORadj 1·03, 95% CI 0·85–1·25; ARRadj −0·3%, 95% CI −2·4 to 1·5) nor extubation at a train-of-four ratio of 0·9 or more (1·03, 0·82–1·31; −0·4%, −3·5 to 2·2) was associated with better pulmonary outcomes. Interpretation: We showed that the use of neuromuscular blocking drugs in general anaesthesia is associated with an increased risk of postoperative pulmonary complications. Anaesthetists must balance the potential benefits of neuromuscular blockade against the increased risk of postoperative pulmonary complications. Funding: European Society of Anaesthesiology.

Published
2019
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29. Increasing motor neuron excitability to treat weakness in sepsis

Author

Randall K. Powers, Timothy C. Cope, Mark M. Rich, and Paul Nardelli

Subjects
0301 basic medicine, Weakness, Voltage clamp, Action Potentials, Article, Lorcaserin, Sepsis, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Computer Simulation, 5-HT receptor, Motor Neurons, Muscle Weakness, business.industry, Benzazepines, Motor neuron, medicine.disease, Rats, Serotonin Receptor Agonists, Motor unit, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, nervous system, Neurology, Neurology (clinical), medicine.symptom, business, Neuroscience, 030217 neurology & neurosurgery, medicine.drug, Serotonin Agonist
Abstract

Objective Weakness induced by critical illness (intensive care unit acquired weakness) is a major cause of disability in patients and is currently untreatable. We recently identified a defect in repetitive firing of lower motor neurons as a novel contributor to intensive care unit acquired weakness. To develop therapy for intensive care unit acquired weakness, it was necessary to determine the mechanism underlying the defect in repetitive firing. Methods Both computer simulation and in vivo dynamic voltage clamp of spinal motor neurons in septic rats were employed to explore potential mechanisms underlying defective repetitive firing. Results Our results suggest alteration in subthreshold voltage-activated currents might be the mechanism underlying defective repetitive firing. It has been shown previously that pharmacologic activation of serotonin receptors on motor neurons increases motor neuron excitability, in part by enhancing subthreshold voltage-activated inward currents. Administration of a U.S. Food and Drug Administration–approved serotonin agonist (lorcaserin) to septic rats greatly improved repetitive firing and motor unit force generation. Interpretation Our findings suggest activation of serotonin receptors with lorcaserin may provide the first ever therapy for intensive care unit acquired weakness in patients. Ann Neurol 2017;82:961–971

Published
2017
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30. Muscle proprioceptors in adult rat: mechanosensory signaling and synapse distribution in spinal cord

Author

Hanna M. Gabriel, Robert E.W. Fyffe, Timothy C. Cope, Jacob A. Vincent, Adam S. Deardorff, Paul Nardelli, and Thomas J. Burkholder

Subjects
0301 basic medicine, Physiology, Muscle spindle, Sensory system, Biology, Synapse, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Distribution (pharmacology), Rats, Wistar, Muscle, Skeletal, Proprioception, General Neuroscience, Spinal cord, Rats, 030104 developmental biology, medicine.anatomical_structure, Spinal Cord, Synapses, Female, Tendon organ, Mechanoreceptors, Neuroscience, 030217 neurology & neurosurgery, Research Article, Muscle Contraction
Abstract

The characteristic signaling and intraspinal projections of muscle proprioceptors best described in the cat are often generalized across mammalian species. However, species-dependent adaptations within this system seem necessary to accommodate asymmetric scaling of length, velocity, and force information required by the physics of movement. In the present study we report mechanosensory responses and intraspinal destinations of three classes of muscle proprioceptors. Proprioceptors from triceps surae muscles in adult female Wistar rats anesthetized with isoflurane were physiologically classified as muscle spindle group Ia or II or as tendon organ group Ib afferents, studied for their firing responses to passive-muscle stretch, and in some cases labeled and imaged for axon projections and varicosities in spinal segments. Afferent projections and the laminar distributions of provisional synapses in rats closely resembled those found in the cat. Afferent signaling of muscle kinematics was also similar to reports in the cat, but rat Ib afferents fired robustly during passive-muscle stretch and Ia afferents displayed an exaggerated dynamic response, even after locomotor scaling was accounted for. These differences in mechanosensory signaling by muscle proprioceptors may represent adaptations for movement control in different animal species.NEW & NOTEWORTHY Muscle sensory neurons signal information necessary for controlling limb movements. The information encoded and transmitted by muscle proprioceptors to networks in the spinal cord is known in detail only for the cat, but differences in size and behavior of other species challenge the presumed generalizability. This report presents the first findings detailing specializations in mechanosensory signaling and intraspinal targets for functionally identified subtypes of muscle proprioceptors in the rat.

Published
2017
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31. Predicting the Risk of Biological Invasions Using Environmental Similarity and Transport Network Connectedness

Author

Phillip Cassey, Michael J. Watts, Joshua V. Ross, Robert C. Cope, and Talia A. Wittmann

Subjects
Matching (statistics), Insecta, Social connectedness, Range (biology), Transport network, Biosecurity, Transport pathways, 0211 other engineering and technologies, 02 engineering and technology, Environment, 010501 environmental sciences, Models, Biological, Risk Assessment, 01 natural sciences, Physiology (medical), Similarity (psychology), Animals, Safety, Risk, Reliability and Quality, Ships, 0105 earth and related environmental sciences, 021110 strategic, defence & security studies, Geography, Ecology, Australia, Reproducibility of Results, 15. Life on land, Air Travel, 13. Climate action, Adaptation, Introduced Species
Abstract

Understanding the risk of biological invasions associated with particular transport pathways and source regions is critical for implementing effective biosecurity management. This may require both a model for physical connectedness between regions, and a measure of environmental similarity, so as to quantify the potential for a species to be transported from a given region and to survive at a destination region. We present an analysis of integrated biosecurity risk into Australia, based on flights and shipping data from each global geopolitical region, and an adaptation of the "range bagging" method to determine environmental matching between regions. Here, we describe global patterns of environmental matching and highlight those regions with many physical connections. We classify patterns of global invasion risk (high to low) into Australian states and territories. We validate our analysis by comparison with global presence data for 844 phytophagous insect pest species, and produce a list of high-risk species not previously known to be present in Australia. We determined that, of the insect pest species used for validation, the species most likely to be present in Australia were those also present in geopolitical regions with high transport connectivity to Australia, and those regions that were geographically close, and had similar environments.

Published
2017
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32. Distribution of TTX-sensitive voltage-gated sodium channels in primary sensory endings of mammalian muscle spindles

Author

Dario I. Carrasco, Timothy C. Cope, and Jacob A. Vincent

Subjects
0301 basic medicine, Sensory Receptor Cells, Physiology, Sodium, Muscle spindle, Action Potentials, chemistry.chemical_element, Sensory system, Tetrodotoxin, Voltage-Gated Sodium Channels, In Vitro Techniques, Antibodies, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Sodium channel blocker, Neurofilament Proteins, Ganglia, Spinal, medicine, Animals, Muscle, Skeletal, Mice, Knockout, Nerve Endings, Afferent Pathways, General Neuroscience, Sodium channel, Myelin Basic Protein, Rats, 030104 developmental biology, medicine.anatomical_structure, chemistry, Cats, Free nerve ending, Neuroscience, 030217 neurology & neurosurgery, Research Article, Sodium Channel Blockers
Abstract

Knowledge of the molecular mechanisms underlying signaling of mechanical stimuli by muscle spindles remains incomplete. In particular, the ionic conductances that sustain tonic firing during static muscle stretch are unknown. We hypothesized that tonic firing by spindle afferents depends on sodium persistent inward current (INaP) and tested for the necessary presence of the appropriate voltage-gated sodium (NaV) channels in primary sensory endings. The NaV1.6 isoform was selected for both its capacity to produce INaP and for its presence in other mechanosensors that fire tonically. The present study shows that NaV1.6 immunoreactivity (IR) is concentrated in heminodes, presumably where tonic firing is generated, and we were surprised to find NaV1.6 IR strongly expressed also in the sensory terminals, where mechanotransduction occurs. This spatial pattern of NaV1.6 IR distribution was consistent for three mammalian species (rat, cat, and mouse), as was tonic firing by primary spindle afferents. These findings meet some of the conditions needed to establish participation of INaP in tonic firing by primary sensory endings. The study was extended to two additional NaV isoforms, selected for their sensitivity to TTX, excluding TTX-resistant NaV channels, which alone are insufficient to support firing by primary spindle endings. Positive immunoreactivity was found for NaV1.1, predominantly in sensory terminals together with NaV1.6 and for NaV1.7, mainly in preterminal axons. Differential distribution in primary sensory endings suggests specialized roles for these three NaV isoforms in the process of mechanosensory signaling by muscle spindles. NEW & NOTEWORTHY The molecular mechanisms underlying mechanosensory signaling responsible for proprioceptive functions are not completely elucidated. This study provides the first evidence that voltage-gated sodium channels (NaVs) are expressed in the spindle primary sensory ending, where NaVs are found at every site involved in transduction or encoding of muscle stretch. We propose that NaVs contribute to multiple steps in sensory signaling by muscle spindles as it does in other types of slowly adapting sensory neurons.

Published
2017
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33. Ant interceptions reveal roles of transport and commodity in identifying biosecurity risk pathways into Australia

Author

Dennis Jefferie O'Dowd, Elissa L. Suhr, Phillip Cassey, Andrew V. Suarez, Talia A. Wittmann, Joshua V. Ross, and Robert C. Cope

Subjects
0106 biological sciences, Linepithema humile, Commodity, Biosecurity, biological invasions, Monomorium pharaonis, Introduced species, Plant Science, Pheidole megacephala, Aquatic Science, introduced ants, 010603 evolutionary biology, 01 natural sciences, Tapinoma melanocephalum, Anoplolepis gracilipes, interception records, lcsh:QH301-705.5, Ecology, Evolution, Behavior and Systematics, Ecology, biology, 010604 marine biology & hydrobiology, Ecological Modeling, Iridomyrmex purpureus, biology.organism_classification, ANT, ports of entry, Geography, lcsh:Biology (General), Insect Science, Animal Science and Zoology
Abstract

We obtained 14,140 interception records of ants arriving in Australia between 1986 and 2010 to examine taxonomic and biogeographic patterns of invasion. We also evaluated how trade and transport data influenced interception rates, the identity of species being transported, the commerce most associated with the transport of ants, and which countries are the primary sources for ants arriving in Australia. The majority of ant interceptions, accounting for 48% of interceptions, were from Asia and Oceania. The top commodities associated with ant interceptions were: (1) Live trees, plants, cut flowers; (2) Wood and wood products; (3) Edible vegetables; and (4) Edible fruit and nuts. The best fitting model for predicting ant interceptions included volumes for these four commodities, as well as total trade value, transport volume, and geographic distance (with increased distance decreasing predicted ant interceptions). Intercepted ants identified to species consisted of a combination of species native to Australia, introduced species already established in Australia, and species not yet known to be established. 82% of interceptions identified to species level were of species already known to be established in Australia withParatrechina longicornishaving the most records. These data provide key biogeographic insight into the overlooked transport stage of the invasion process. Given the difficult nature of eradication, once an ant species is firmly established, focusing on early detection and quarantine is key for reducing the establishment of new invasions.

Published
2019

34. Elucidating user behaviours in a digital health surveillance system to correct prevalence estimates

Author

Sandra J. Carlson, Dennis Liu, Joshua V. Ross, Robert C. Cope, and Lewis Mitchell

Subjects
medicine.medical_specialty, Epidemiology, Computer science, Process (engineering), 030231 tropical medicine, Bayesian statistics, Bayesian inference, Microbiology, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Consistency (database systems), 0302 clinical medicine, Virology, Human behaviour, Influenza, Human, Prevalence, medicine, Humans, lcsh:RC109-216, 030212 general & internal medicine, Sampling bias, Public health, Australia, Public Health, Environmental and Occupational Health, Sampling (statistics), Bayes Theorem, Citizen journalism, Data science, Digital health, Infectious Diseases, Digital data, Epidemiological Monitoring, Parasitology, Public Health
Abstract

Estimating seasonal influenza prevalence is of undeniable public health importance, but remains challenging with traditional datasets due to cost and timeliness. Digital epidemiology has the potential to address this challenge, but can introduce sampling biases that are distinct to traditional systems. In online participatory health surveillance systems, the voluntary nature of the data generating process must be considered to address potential biases in estimates. Here we examine user behaviours in one such platform, FluTracking, from 2011 to 2017. We build a Bayesian model to estimate probabilities of an individual reporting in each week, given their past reporting behaviour, and to infer the weekly prevalence of influenza-like-illness (ILI) in Australia. We show that a model that corrects for user behaviour can substantially effect ILI estimates. The model examined here elucidates several factors, such as the status of having ILI and consistency of prior reporting, that are strongly associated with the likelihood of participating in online health surveillance systems. This framework could be applied to other digital participatory health systems where participation is inconsistent and sampling bias may be of concern.

Published
2019
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35. On the probability of strain invasion in endemic settings: accounting for individual heterogeneity and control in multi-strain dynamics

Author

Michael T. Meehan, Emma S. McBryde, and Robert C. Cope

Subjects
0301 basic medicine, Statistics and Probability, Population, Branching process, Biology, Pathogen evolution, Anti-microbial drug resistance, Article, General Biochemistry, Genetics and Molecular Biology, Disease Outbreaks, law.invention, Strain invasion, 03 medical and health sciences, 0302 clinical medicine, law, Global health, Epidemic control, Multi-strain, Epidemics, Control (linguistics), education, Quantitative Biology - Populations and Evolution, Probability, education.field_of_study, General Immunology and Microbiology, Individual heterogeneity, Applied Mathematics, Strain (biology), fungi, Populations and Evolution (q-bio.PE), food and beverages, Outbreak, General Medicine, 030104 developmental biology, Transmission (mechanics), Evolutionary biology, Modeling and Simulation, FOS: Biological sciences, General Agricultural and Biological Sciences, 030217 neurology & neurosurgery
Abstract

The rise of antimicrobial drug resistance is an imminent threat to global health that has warranted, and duly received, considerable attention within the medical, microbiological and modelling communities. Outbreaks of drug-resistant pathogens are ignited by the emergence and transmission of mutant variants descended from wild-type strains circulating in the community. In this work we investigate the stochastic dynamics of the emergence of a novel disease strain, introduced into a population in which it must compete with an existing endemic strain. In analogy with past work on single-strain epidemic outbreaks, we apply a branching process approximation to calculate the probability that the new strain becomes established. As expected, a critical determinant of the survival prospects of any invading strain is the magnitude of its reproduction number relative to that of the background endemic strain. Whilst in most circumstances this ratio must exceed unity in order for invasion to be viable, we show that differential control scenarios can lead to less-fit novel strains invading populations hosting a fitter endemic one. This analysis and the accompanying findings will inform our understanding of the mechanisms that have led to past instances of successful strain invasion, and provide valuable lessons for thwarting future drug-resistant strain incursions., 32 pages, 5 figures

Published
2019

36. Cancer Exacerbates Chemotherapy Induced Sensory Neuropathy

Author

Emily Pfahl, Lilya V. Matyunina, Dario I. Carrasco, Stephen N. Housley, Paul Nardelli, John F. McDonald, and Timothy C. Cope

Subjects
0303 health sciences, Chemotherapy, business.industry, medicine.medical_treatment, Sensory system, medicine.disease, Sensory neuron, Potassium channel, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Peripheral neuropathy, Chemotherapy induced, Chemotherapy-induced peripheral neuropathy, medicine, Sensory neuropathy, business, Neuroscience, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

For the constellation of neurological disorders known as chemotherapy induced peripheral neuropathy, mechanistic understanding, and treatment remain deficient. Here we present the first evidence in preclinical investigation of rats that chronic sensory neuropathy depends on non-linear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as a potential contributor to sensory neuron dysfunction. These original findings identify novel contributors to peripheral neuropathy, and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer.

Published
2019
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37. Dysregulation of Mechanosensory Circuits Coordinating the Actions of Antagonist Motor Pools Following Peripheral Nerve Injury and Muscle Reinnervation

Author

Timothy C. Cope, Stephen N. Housley, and Gabrielle Marie Horstman

Subjects
0301 basic medicine, Reflex, Stretch, Article, 03 medical and health sciences, 0302 clinical medicine, Developmental Neuroscience, Peripheral Nerve Injuries, Neural Pathways, Medicine, Animals, Stretch reflex, Rats, Wistar, Muscle, Skeletal, Spinal cord injury, business.industry, Antagonist, Reciprocal inhibition, Nerve injury, medicine.disease, Nerve Regeneration, Rats, 030104 developmental biology, medicine.anatomical_structure, Neurology, Spinal Cord, Peripheral nerve injury, Reflex, Female, medicine.symptom, business, Neuroscience, 030217 neurology & neurosurgery, Reinnervation
Abstract

Movement disorders observed following peripheral nerve injury and muscle reinnervation suggest discoordination in the activation of antagonist muscles. Although underlying mechanisms remain undecided, dysfunction in spinal reflex circuits is a reasonable candidate. Based on the well known role of reflex inhibition between agonist and antagonist muscles in normal animals, we hypothesized its reduction following muscle reinnervation, similar to that associated with other disorders exhibiting antagonist discoordination, e.g. spinal cord injury and dystonia. Experiments performed on acutely-decerebrated rats examined interactions of mechanosensory reflexes between ipsilateral muscles acting as mechanical antagonists at the ankle joint: ankle extensor, gastrocnemii (G) muscles (agonists) and ankle flexor, tibialis anterior (TA) muscle (antagonist). The force of agonist stretch reflex contraction was measured for its suppression or facilitation by concurrent conditioning stretch of the antagonist muscle. Data were compared between two groups of adult rats, an antagonist reinnervation group with TA muscle reinnervated and a control group with TA normally innervated. Results revealed a three-fold increase in reflex suppression in the antagonist reinnervation group, contrary to our predicted decrease. Reflex facilitation also increased, not only in strength, seven-fold, but also in its frequency of stochastic occurrence across stimulus trials. These observations suggest dysregulation in specific spinal reflex circuits as novel candidate origins of modified antagonist muscle coordination following peripheral nerve injury and muscle reinnervation.

Published
2019

38. Creating Wildflower Habitats in Golf Course Out-Of-Play Areas

Author

Rebecca Nestle, Adam G. Dale, Nicole D. Benda, and Grace C. Cope

Subjects
Geography, Wildflower, Habitat, Ecology, Course (navigation)
Abstract

Habitat loss from urbanization and agricultural intensification is reducing native bee and monarch butterfly populations, but golf courses in urban areas present an opportunity to mitigate the negative effects of urbanization on pollinators and the environment. It is feasible to enhance a golf course’s ability to support more species and a greater abundance of wildlife by planting the 40% to 70% of acreage not used for the game of golf in wildflowers. With the most golf courses of any US state, Florida is poised to set the stage for golf course environmental stewardship. This 8-page fact sheet written by Rebecca Nestle, Grace Cope, Nicole Benda, and Adam G. Dale and published by the UF/IFAS Entomology and Nematology Department is intended to provide guidelines for Florida golf course superintendents to aid in their efforts to conserve important wildlife while reducing maintenance inputs and associated costs. https://edis.ifas.ufl.edu/in1316

Published
2021
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39. A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encoding

Author

Krystyna Blanka Wieczerzak, Timothy C. Cope, Mark M. Rich, Hanna M. Gabriel, Jacob A. Vincent, and Paul Nardelli

Subjects
0301 basic medicine, Organoplatinum Compounds, Sensory Receptor Cells, Stimulation, Sensory system, muscle proprioceptors, Article, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Sensory ataxia, Dorsal root ganglion, Ganglia, Spinal, medicine, Neurotoxicity, Animals, Chemotherapy, Rats, Wistar, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Proprioception, business.industry, Antagonist, Peripheral Nervous System Diseases, medicine.disease, Riluzole, Neuropathy, Oxaliplatin, 030104 developmental biology, medicine.anatomical_structure, Neurology, Sensorimotor deficits, Anesthesia, Female, Neurotoxicity Syndromes, medicine.symptom, business, Neuroscience, 030217 neurology & neurosurgery, Signal Transduction, medicine.drug
Abstract

Persistent neurotoxic side effects of Oxaliplatin (OX) chemotherapy, including sensory ataxia, limit the efficacy of treatment and significantly diminish patient quality of life. The common explanation for neurotoxicity is neuropathy, however the degree of neuropathy varies greatly among patients and appears insufficient in some cases to fully account for disability. We recently identified an additional mechanism that might contribute to sensory ataxia following OX treatment. In the present study, we tested whether that mechanism, selective modification of sensory signaling by muscle proprioceptors might result in behavioral deficits in rats. OX was administered once per week for seven weeks (cumulative dose i.p. 70 mg/kg) to adult female Wistar rats. Throughout and for three weeks following treatment, behavioral analysis was performed daily on OX and sham control rats. Compared to controls, OX rats demonstrated errors in placing their hind feet securely and/or correctly during a horizontal ladder rung task. These behavioral deficits occurred together with modification of proprioceptor signaling that eliminated sensory encoding of static muscle position while having little effect on encoding of dynamic changes in muscle length. Selective inability to sustain repetitive firing in response to static muscle stretch led us to hypothesize that OX treatment impairs specific ionic currents, possibly the persistent inward Na currents (NaPIC) that are known to support repetitive firing during static stimulation in several neuron types, including the class of large diameter dorsal root ganglion cells that includes muscle proprioceptors. We tested this hypothesis by determining whether the chronic effects of OX on the firing behavior of muscle proprioceptors in vivo were mimicked by acute injection of NaPIC antagonists. Both riluzole and phenytoin, each having multiple drug actions but having only antagonist action on NaPIC in common, reproduced selective modification of proprioceptor signaling observed in OX rats. Taken together, these findings lead us to propose that OX chemotherapy contributes to movement disability by modifying sensory encoding, possibly via a chronic neurotoxic effect on NaPIC in the sensory terminals of muscle proprioceptors.

Published
2016

40. A global analysis of the determinants of alien geographical range size in birds

Author

Phillip Cassey, Tim M. Blackburn, Çağan H. Şekercioğlu, Robert C. Cope, Victoria R. Franks, Kate E. Jones, Ellie E. Dyer, and Ben Collen

Subjects
0106 biological sciences, Global and Planetary Change, Ecology, Range (biology), 010604 marine biology & hydrobiology, Niche, Alien, Biology, 010603 evolutionary biology, 01 natural sciences, Invasive species, Colonization, Economic impact analysis, Alien species, Ecology, Evolution, Behavior and Systematics
Abstract

Aim Determining the causes of range size variation in the distributions of alien species is important for understanding the spread of invasive species. Factors influencing alien range size have been explored for some species at a regional level, but to date there has been no global analysis of an entire class. Here, we present such an analysis for birds, testing for the effects of introduction event, location and species-level variables on alien range sizes. Location Global. Methods We used a novel dataset on the global distributions of alien bird species to test for relationships between alien range size and colonization pressure, residence time, extent of the global climatic niche, native range size, body mass and specialization, using a statistical approach based on phylogenetic generalized least squares models. We performed this analysis globally, and for separate biogeographical realms. Results Approximately half of the variation in alien bird range size is explained by colonization pressure in univariate analysis. We identified consistent effects of higher colonization pressure at global and realm levels, as well as support for effects of native range size and residence time. We found less support for effects of body mass, specialization or extent of the global climatic niche on alien range size. Main conclusions Alien bird range sizes are generally small relative to their native range sizes, and many are continuing to expand. Nevertheless, current variation is predictable, most strongly by the event-level factor of colonization pressure. Whether a species is widespread is a better predictor of alien range size than whether a species could be widespread (estimated by global climatic niche extent), while we also find effects of residence time on alien range size. These relationships may help to identify those alien species that are more likely to spread and hence have greater environmental and economic impacts where they have been introduced.

Published
2016
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41. Reduced motor neuron excitability is an important contributor to weakness in a rat model of sepsis

Author

Paul Nardelli, Jacob A. Vincent, Timothy C. Cope, Randall K. Powers, and Mark M. Rich

Subjects
Weakness, Patch-Clamp Techniques, Neuromuscular transmission, Action Potentials, Synaptic Transmission, Article, Neuromuscular junction, Sepsis, 03 medical and health sciences, 0302 clinical medicine, Developmental Neuroscience, medicine, Animals, Myopathy, Motor Neurons, Analysis of Variance, Muscle Weakness, Electromyography, business.industry, 030208 emergency & critical care medicine, Motor neuron, medicine.disease, Electric Stimulation, Rats, Motor unit, Disease Models, Animal, medicine.anatomical_structure, Spinal Cord, nervous system, Neurology, Motor unit recruitment, medicine.symptom, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in patients as a novel contributor to ICUAW. To study the mechanism underlying poor recruitment of motor units we used the rat cecal ligation and puncture model of sepsis. We identified striking dysfunction of alpha motor neurons during repetitive firing. Firing was more erratic, and often intermittent. Our data raised the possibility that reduced excitability of motor neurons was a significant contributor to weakness induced by sepsis. In this study we quantified the contribution of reduced motor neuron excitability and compared its magnitude to the contributions of myopathy, neuropathy and failure of neuromuscular transmission. We injected constant depolarizing current pulses (5 sec) into the soma of alpha motor neurons in the lumbosacral spinal cord of anesthetized rats to trigger repetitive firing. In response to constant depolarization, motor neurons in untreated control rats fired at steady and continuous firing rates and generated smooth and sustained tetanic motor unit force as expected. In contrast, following induction of sepsis, motor neurons were often unable to sustain firing throughout the 5s current injection such that force production was reduced. Even when firing, motor neurons from septic rats fired erratically and discontinuously, leading to irregular production of motor unit force. Both fast and slow type motor neurons had similar disruption of excitability. We followed rats after recovery from sepsis to determine the time course of resolution of the defect in motor neuron excitability. By one week, rats appeared to have recovered from sepsis as they had no piloerection and appeared to be in no distress. The defects in motor neuron repetitive firing were still striking at 2 weeks and, although improved, were present at one month. We infer that rats suffered from weakness due to reduced motor neuron excitability for weeks after resolution of sepsis. To assess whether additional contributions from myopathy, neuropathy and defects in neuromuscular transmission contributed to the reduction in force generation, we measured whole-muscle force production in response to electrical stimulation of the muscle nerve. We found no abnormality in force generation that would suggest the presence of myopathy, neuropathy or defective neuromuscular transmission. These data suggest disruption of repetitive firing of motor neurons is an important contributor to weakness induced by sepsis in rats and raise the possibility that reduced motor neuron excitability contributes to disability that persists after resolution of sepsis.

Published
2016
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42. Adult-Born Neurons in the Hippocampus Are Essential for Social Memory Maintenance

Author

Emma J. Diethorn, Elise C. Cope, Renee C. Waters, Mumeko C. Tsuda, Heather A. Cameron, Kristen A Pagliai, Elizabeth Gould, and Carla G Dias

Subjects
Genetically modified mouse, social memory, Social memory, hippocampus, Neurogenesis, social dominance, Transgene, Research Article: Confirmation, Mice, Transgenic, Biology, Hippocampal formation, TK-GFAP, Mice, Memory, medicine, Animals, Neurons, General Neuroscience, Dentate gyrus, General Medicine, adult neurogenesis, Dominance hierarchy, Cognition and Behavior, Dentate Gyrus, Anxiety, medicine.symptom, Neuroscience
Abstract

Throughout adulthood, the dentate gyrus continues to produce new granule cells, which integrate into the hippocampal circuitry. New neurons have been linked to several known functions of the hippocampus, including learning and memory, anxiety and stress regulation, and social behavior. We explored whether transgenic reduction of adult-born neurons in mice would impair social memory and the formation of social dominance hierarchies. We used a conditional transgenic mouse strain [thymidine kinase (TK) mice] that selectively reduces adult neurogenesis by treatment with the antiviral drug valganciclovir (VGCV). TK mice treated with VGCV were unable to recognize conspecifics as familiar 24 h after initial exposure. We then explored whether reducing new neurons completely impaired their ability to acquire or retrieve a social memory and found that TK mice treated with VGCV were able to perform at control levels when the time between exposure (acquisition) and reexposure (retrieval) was brief. We next explored whether adult-born neurons are involved in dominance hierarchy formation by analyzing their home cage behavior as well as their performance in the tube test, a social hierarchy test, and did not find any consistent alterations in behavior between control and TK mice treated with VGCV. These data suggest that adult neurogenesis is essential for social memory maintenance, but not for acquisition nor retrieval over a short time frame, with no effect on social dominance hierarchy. Future work is needed to explore whether the influence of new neurons on social memory is mediated through connections with the CA2, an area involved in social recognition.

Published
2020
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43. Noncontractile tissue forces mask muscle fiber forces underlying muscle spindle Ia afferent firing rates in stretch of relaxed rat muscle

Author

Paul Nardelli, Timothy C. Cope, Lena H. Ting, and Kyle P. Blum

Subjects
medicine.anatomical_structure, CATS, Chemistry, Tissue Model, Muscle spindle, medicine, Ia afferent, Anatomy, Muscle fibre, Muscle force
Abstract

Stretches of relaxed cat and rat muscle elicit similar history-dependent muscle spindle Ia firing rates that resemble history-dependent forces seen in single activated muscle fibers (Nichols and Cope, 2004). During stretch of relaxed cat muscle, whole musculotendon forces exhibit history-dependence that mirror history-dependent muscle spindle firing rates, where both muscle force and muscle spindle firing rates are elevated in the first stretch in a series of stretch-shorten cycles (Blum et al., 2017). By contrast, rat musculotendon are only mildly history-dependent and do not mirror history-dependent muscle spindle firing rates in the same way (Haftel et al., 2004). We hypothesized that history-dependent muscle spindle firing rates elicited in stretch of relaxed rat muscle would mirror history-dependent muscle fiber forces, which are masked by noncontractile tissue at the level of whole musculotendon force. We removed noncontractile tissue force contributions from the recorded musculotendon force using an exponentially-elastic tissue model. We then show that the remaining estimated muscle fiber force resembles history-dependent muscle spindle firing rates recorded simultaneously. These forces also resemble history-dependent forces recorded in stretch of single activated fibers and attributed to muscle cross-bridge mechanisms (Campbell and Moss, 2000). Our results suggest that history-dependent muscle spindle firing in both rats and cats arise from stretch of cross-bridges in muscle fibers.

Published
2018
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44. Elastic tissue forces mask muscle fiber forces underlying muscle spindle Ia afferent firing rates in stretch of relaxed rat muscle

Author

Paul Nardelli, Timothy C. Cope, Lena H. Ting, and Kyle P. Blum

Subjects
0106 biological sciences, Physiology, 030310 physiology, Short Communication, Muscle spindle, Muscle Fibers, Skeletal, Ia afferent, Aquatic Science, Somatosensory system, 010603 evolutionary biology, 01 natural sciences, 03 medical and health sciences, medicine, Animals, Neurons, Afferent, Muscle fibre, Rats, Wistar, Muscle, Skeletal, Molecular Biology, Muscle Spindles, Ecology, Evolution, Behavior and Systematics, Muscle force, 0303 health sciences, Proprioception, Chemistry, Tissue Model, Elastic Tissue, Sensorimotor control, medicine.anatomical_structure, Insect Science, Biophysics, Animal Science and Zoology, Female, Muscle Contraction
Abstract

Stretches of relaxed cat and rat muscle elicit similar history-dependent muscle spindle Ia firing rates that resemble history-dependent forces seen in single activated muscle fibers ( Nichols and Cope, 2004). Owing to thixotropy, whole musculotendon forces and muscle spindle firing rates are history dependent during stretch of relaxed cat muscle, where both muscle force and muscle spindle firing rates are elevated in the first stretch in a series of stretch–shorten cycles ( Blum et al., 2017). By contrast, rat musculotendon exhibits only mild thixotropy, such that the measured forces when stretched cannot explain history-dependent muscle spindle firing rates in the same way ( Haftel et al., 2004). We hypothesized that history-dependent muscle spindle firing rates elicited in stretch of relaxed rat muscle mirror history-dependent muscle fiber forces, which are masked at the level of whole musculotendon force by extracellular tissue force. We removed estimated extracellular tissue force contributions from recorded musculotendon force using an exponentially elastic tissue model. We then showed that the remaining estimated muscle fiber force resembles history-dependent muscle spindle firing rates recorded simultaneously. These forces also resemble history-dependent forces recorded in stretch of single activated fibers that are attributed to muscle cross-bridge mechanisms ( Campbell and Moss, 2000). Our results suggest that history-dependent muscle spindle firing in both rats and cats arise from history-dependent forces owing to thixotropy in muscle fibers.

Published
2018

45. Connecting surveillance and population-level influenza incidence

Author

Joshua V. Ross, Lewis Mitchell, Robert C. Cope, Monique Chilver, and Nigel Stocks

Subjects
medicine.medical_specialty, Surveillance data, Population level, business.industry, Incidence (epidemiology), Environmental health, Assessment methods, Epidemiology, virus diseases, Medicine, business
Abstract

There is substantial interest in estimating and forecasting influenza incidence. Surveillance of influenza is challenging as one needs to demarcate influenza from other respiratory viruses, and due to asymptomatic infections. To circumvent these challenges, surveillance data often targets influenza-like-illness, or uses context-specific normalisations such as test positivity or per-consultation rates. Specifically, influenza incidence itself is not reported. We propose a framework to estimate population-level influenza incidence, and its associated uncertainty, using surveillance data and hierarchical observation processes. This new framework, and forecasting and forecast assessment methods, are demonstrated for three Australian states over 2016 and 2017. The framework allows for comparison within and between seasons in which surveillance effort has varied. Implementing this framework would improve influenza surveillance and forecasting globally, and could be applied to other diseases for which surveillance is difficult.

Published
2018
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46. New functions for the proprioceptive system in skeletal biology

Author

Robert W. Banks, Elazar Zelzer, Lia Heinemann-Yerushalmi, Guy S. Bewick, Nitzan Konstantin, Eran Assaraf, Ronen Blecher, Jens R. Chapman, and Timothy C. Cope

Subjects
0301 basic medicine, Muscle spindle, Sensory system, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, symbols.namesake, Mice, 0302 clinical medicine, Skeletal biology, medicine, Animals, Humans, Receptor, Muscle, Skeletal, Muscle Spindles, Proprioception, Articles, Golgi apparatus, Spine, Tendon, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Scoliosis, symbols, General Agricultural and Biological Sciences, Neuroscience, Mechanoreceptors, 030217 neurology & neurosurgery
Abstract

Muscle spindles and Golgi tendon organs (GTOs) are two types of sensory receptors that respond to changes in length or tension of skeletal muscles. These mechanosensors have long been known to participate in both proprioception and stretch reflex. Here, we present recent findings implicating these organs in maintenance of spine alignment as well as in realignment of fractured bones. These discoveries have been made in several mouse lines lacking functional mechanosensors in part or completely. In both studies, the absence of functional spindles and GTOs produced a more severe phenotype than that of spindles alone. Interestingly, the spinal curve phenotype, which appeared during peripubertal development, bears resemblance to the human condition adolescent idiopathic scoliosis. This similarity may contribute to the study of the disease by offering both an animal model and a clue as to its aetiology. Moreover, it raises the possibility that impaired proprioceptive signalling may be involved in the aetiology of other conditions. Overall, these new findings expand considerably the scope of involvement of proprioception in musculoskeletal development and function.This article is part of the Theo Murphy meeting issue ‘Mechanics of development’.

Published
2018

47. Progressive adaptation of whole-limb kinematics after peripheral nerve injury

Author

Young-Hui Chang, Stephen N. Housley, Huub Maas, Kerry S. Hart, Paul Nardelli, Richard Nichols, Timothy C. Cope, Neuromechanics, AMS - Restoration and Development, and AMS - Fundamental Research

Subjects
0301 basic medicine, medicine.medical_specialty, QH301-705.5, Science, Kinematics, Biology, General Biochemistry, Genetics and Molecular Biology, Injury response, Compensation strategy, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, SDG 3 - Good Health and Well-being, Peripheral nerve, Muscle paralysis, medicine, Biology (General), Functional recovery, Locomotor compensation, Nerve injury, 030104 developmental biology, medicine.anatomical_structure, Peripheral nerve injury, medicine.symptom, Ankle, General Agricultural and Biological Sciences, 030217 neurology & neurosurgery, Research Article
Abstract

The ability to recover purposeful movement soon after debilitating neuromuscular injury is essential to animal survival. Various neural and mechanical mechanisms exist to preserve whole-limb kinematics despite exhibiting long-term deficits of individual joints following peripheral nerve injury. However, it is unclear whether functionally relevant whole-limb movement is acutely conserved following injury. Therefore, the objective of this longitudinal study of the injury response from four individual cats was to test the hypothesis that whole-limb length is conserved following localized nerve injury of ankle extensors in cats with intact nervous systems. The primary finding of our study was that whole-limb kinematics during walking was not immediately preserved following peripheral nerve injuries that paralyzed subsets of ankle extensor muscles. Instead, whole-limb kinematics recovered gradually over multiple weeks, despite having the mechanical capacity of injury-spared muscles across all joints to achieve immediate functional recovery. The time taken to achieve complete recovery of whole-limb kinematics is consistent with an underlying process that relies on neuromuscular adaptation. Importantly, the gradual recovery of ankle joint kinematics remained incomplete, discontinuing once whole-limb kinematics had fully recovered. These findings support the hypothesis that a whole-limb representation of healthy limb function guides a locomotor compensation strategy after neuromuscular injury that arrests progressive changes in the joint kinematics once whole-limb kinematics is regained., Summary: Longitudinal study of four cats documented recovery of locomotor kinematics in one hindlimb following nerve injury and muscle paralysis focused at the ankle joint. Whole-limb length was not conserved immediately, but recovered pre-injury levels gradually through kinematic adjustments distributed across joints.

Published
2018
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48. Real-time Detection of Content Polluters in Partially Observable Twitter Networks

Author

Lewis Mitchell, Mehwish Nasim, Robert C. Cope, Nick Lothian, and Andrew Nguyen

Subjects
Social and Information Networks (cs.SI), FOS: Computer and information sciences, Social network, business.industry, Computer science, Event (computing), media_common.quotation_subject, Network data, Computer Science - Social and Information Networks, 02 engineering and technology, Data science, Identification (information), 020204 information systems, Content (measure theory), 0202 electrical engineering, electronic engineering, information engineering, 020201 artificial intelligence & image processing, Social media, Conversation, Research questions, business, media_common
Abstract

Content polluters, or bots that hijack a conversation for political or advertising purposes are a known problem for event prediction, election forecasting and when distinguishing real news from fake news in social media data. Identifying this type of bot is particularly challenging, with state-of-the-art methods utilising large volumes of network data as features for machine learning models. Such datasets are generally not readily available in typical applications which stream social media data for real-time event prediction. In this work we develop a methodology to detect content polluters in social media datasets that are streamed in real-time. Applying our method to the problem of civil unrest event prediction in Australia, we identify content polluters from individual tweets, without collecting social network or historical data from individual accounts. We identify some peculiar characteristics of these bots in our dataset and propose metrics for identification of such accounts. We then pose some research questions around this type of bot detection, including: how good Twitter is at detecting content polluters and how well state-of-the-art methods perform in detecting bots in our dataset., Accepted for publication in WWW '18 Companion: The 2018 Web Conference Companion, April 23-27, 2018, Lyon, France

Published
2018

49. Ethical dilemmas and reflexivity in qualitative research

Author

Jeremy Brown, Anne-Marie Reid, Alexandra C. Cope, Susan Jamieson, and Julie M. Smith

Subjects
Value (ethics), 020205 medical informatics, media_common.quotation_subject, Practitioner research, 02 engineering and technology, Altruism, Peer Group, Role conflict, Ethics, Research, Education, 03 medical and health sciences, 0302 clinical medicine, Empirical research, Reflexivity, 0202 electrical engineering, electronic engineering, information engineering, Humans, 030212 general & internal medicine, Sociology, Situational ethics, Qualitative Research, media_common, Publishing, ComputingMilieux_THECOMPUTINGPROFESSION, Professionalism, Commentary, Engineering ethics, Qualitative research
Abstract

Context For medical education researchers, a key concern may be the practicalities of gaining ethical approval where this is a national or local requirement. However, in qualitative studies, where the dynamics of human interaction pervade, ethical considerations are an ongoing process which continues long after approval has been granted. Responding to ethical dilemmas arising ‘in the moment’ requires a reflexive approach whereby the researcher questions his/her own motivations, assumptions and interests. Drawing on empirical studies and their experiences in academic and clinical research practice, the authors share their reflections on adhering to ethical principles throughout the research process to illustrate the complexities and nuances involved. Objectives and findings These reflections offer critical insights into dilemmas arising in view of the ethical principles driving good conduct, and through domains which distinguish between procedural ethics, situational ethics, ethical relationships and ethical issues in exiting the study. The accounts consider integrity and altruism in research, gatekeeping and negotiating access, consent and confidentiality, power dynamics and role conflict, and challenges in dissemination of findings. The experiences are based on a range of examples of research in a UK context from managing difficult conversations in the classroom to video-ethnography in the operating theatre. Discussion and conclusions These critical reflections make visible the challenges encountered and decisions that must be taken in the moment and on reflection after the event. Through sharing our experiences and debating the decisions we made, we offer insights into reflexivity in qualitative research which will be of value to others.

Published
2018

50. Complex impairment of IA muscle proprioceptors following traumatic or neurotoxic injury

Author

Timothy C. Cope, Paul Nardelli, Hanna M. Gabriel, Jacob A. Vincent, and Adam S. Deardorff

Subjects
Male, Histology, Movement disorders, Sensory Receptor Cells, Muscle spindle, Sensory system, Peripheral Nerve Injuries, medicine, Animals, Neurons, Afferent, Muscle Spindles, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Motor Neurons, Movement Disorders, Proprioception, business.industry, Cell Biology, Anatomy, medicine.disease, Spinal cord, Rats, Electrophysiology, Proprioceptive function, Neuroprotective Agents, Peripheral neuropathy, medicine.anatomical_structure, Spinal Cord, Original Article, Female, medicine.symptom, business, Neuroscience, Signal Transduction, Developmental Biology
Abstract

The health of primary sensory afferents supplying muscle has to be a first consideration in assessing deficits in proprioception and related motor functions. Here we discuss the role of a particular proprioceptor, the IA muscle spindle proprioceptor in causing movement disorders in response to either regeneration of a sectioned peripheral nerve or damage from neurotoxic chemotherapy. For each condition, there is a single preferred and widely repeated explanation for disability of movements associated with proprioceptive function. We present a mix of published and preliminary findings from our laboratory, largely from in vivo electrophysiological study of treated rats to demonstrate newly discovered IA afferent defects that seem likely to make important contributions to movement disorders. First, we argue that reconnection of regenerated IA afferents with inappropriate targets, although often repeated as the reason for lost stretch-reflex contraction, is not a complete explanation. We present evidence that despite successful recovery of stretch-evoked sensory signaling, peripherally regenerated IA afferents retract synapses made with motoneurons in the spinal cord. Second, we point to evidence that movement disability suffered by human subjects months after discontinuation of oxaliplatin (OX) chemotherapy for some is not accompanied by peripheral neuropathy, which is the acknowledged primary cause of disability. Our studies of OX-treated rats suggest a novel additional explanation in showing the loss of sustained repetitive firing of IA afferents during static muscle stretch. Newly extended investigation reproduces this effect in normal rats with drugs that block Na(+) channels apparently involved in encoding static IA afferent firing. Overall, these findings highlight multiplicity in IA afferent deficits that must be taken into account in understanding proprioceptive disability, and that present new avenues and possible advantages for developing effective treatment. Extending the study of IA afferent deficits yielded the additional benefit of elucidating normal processes in IA afferent mechanosensory function.

Published
2015
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