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1. Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trialResearch in context

Author

Laure F. Pittet, Nicole L. Messina, Ellie McDonald, Francesca Orsini, Simone Barry, Marc Bonten, John Campbell, Julio Croda, Mariana G. Croda, Margareth Dalcolmo, Kaya Gardiner, Amanda Gwee, Bruno Jardim, Marcus V.G. Lacerda, Michaela Lucas, David J. Lynn, Laurens Manning, Kirsten P. Perrett, Jeffrey J. Post, Cristina Prat-Aymerich, Peter C. Richmond, Jorge L. Rocha, Jesus Rodriguez-Baño, Adilia Warris, Nicholas J. Wood, Andrew Davidson, Nigel Curtis, Tenaya Jamieson, Nicole Messina, Thilanka Morawakage, Susan Perlen, Kirsten Perrett, Laure Pittet, Amber Sastry, Jia Wei Teo, Katherine Lee, Cecilia Moore, Suzanna Vidmar, Rashida Ali, Ross Dunn, Peta Edler, Grace Gell, Casey Goodall, Richard Hall, Ann Krastev, Nathan La, Nick McPhate, Thao Nguyen, Jack Ren, Luke Stevens, Ahmed Alamrousi, Rhian Bonnici, Thanh Dang, Susie Germano, Jenny Hua, Rebecca McElroy, Monica Razmovska, Scott Reddiex, Xiaofang Wang, Jeremy Anderson, Kristy Azzopardi, Vicki Bennett-Wood, Anna Czajko, Nadia Mazarakis, Conor McCafferty, Frances Oppedisano, Belinda Ortika, Casey Pell, Leena Spry, Ryan Toh, Sunitha Velagapudi, Amanda Vlahos, Ashleigh Wee-Hee, Pedro Ramos, Karina De La Cruz, Dinusha Gamage, Anushka Karunanayake, Isabella Mezzetti, Benjamin Ong, Ronita Singh, Enoshini Sooriyarachchi, Suellen Nicholson, Natalie Cain, Rianne Brizuela, Han Huang, Veronica Abruzzo, Morgan Bealing, Patricia Bimboese, Kirsty Bowes, Emma Burrell, Joyce Chan, Jac Cushnahan, Hannah Elborough, Olivia Elkington, Kieran Fahey, Monique Fernandez, Catherine Flynn, Sarah Fowler, Marie Gentile Andrit, Bojana Gladanac, Catherine Hammond, Norine Ma, Sam Macalister, Emmah Milojevic, Jesutofunmi Mojeed, Jill Nguyen, Liz O'Donnell, Nadia Olivier, Isabelle Ooi, Stephanie Reynolds, Lisa Shen, Barb Sherry, Judith Spotswood, Jamie Wedderburn, Angela Younes, Donna Legge, Jason Bell, Jo Cheah, Annie Cobbledick, Kee Lim, Sonja Elia, Lynne Addlem, Anna Bourke, Clare Brophy, Nadine Henare, Narelle Jenkins, Francesca Machingaifa, Skye Miller, Kirsten Mitchell, Sigrid Pitkin, Kate Wall, Paola Villanueva, Nigel Crawford, Wendy Norton, Niki Tan, Thilakavathi Chengodu, Diane Dawson, Victoria Gordon, Tony Korman, Jess O'Bryan, Sophie Agius, Samantha Bannister, Jess Bucholc, Alison Burns, Beatriz Camesella, John Carlin, Marianna Ciaverella, Maxwell Curtis, Stephanie Firth, Christina Guo, Matthew Hannan, Erin Hill, Sri Joshi, Katherine Lieschke, Megan Mathers, Sasha Odoi, Ashleigh Rak, Chris Richards, Leah Steve, Carolyn Stewart, Eva Sudbury, Helen Thomson, Emma Watts, Fiona Williams, Angela Young, Penny Glenn, Andrew Kaynes, Amandine Philippart De Floy, Sandy Buchanan, Thijs Sondag, Ivy Xie, Harriet Edmund, Bridie Byrne, Tom Keeble, Belle Ngien, Fran Noonan, Michelle Wearing-Smith, Alison Clarke, Pemma Davies, Oliver Eastwood, Alric Ellinghaus, Rachid Ghieh, Zahra Hilton, Emma Jennings, Athina Kakkos, Iris Liang, Katie Nicol, Sally O'Callaghan, Helen Osman, Gowri Rajaram, Sophia Ratcliffe, Victoria Rayner, Ashleigh Salmon, Angela Scheppokat, Aimee Stevens, Rebekah Street, Nicholas Toogood, Nicholas Wood, Twinkle Bahaduri, Therese Baulman, Jennifer Byrne, Candace Carter, Mary Corbett, Aiken Dao, Maria Desylva, Andrew Dunn, Evangeline Gardiner, Rosemary Joyce, Rama Kandasamy, Craig Munns, Lisa Pelayo, Ketaki Sharma, Katrina Sterling, Caitlin Uren, Clinton Colaco, Mark Douglas, Kate Hamilton, Adam Bartlett, Brendan McMullan, Pamela Palasanthiran, Phoebe Williams, Justin Beardsley, Nikki Bergant, Renier Lagunday, Kristen Overton, Jeffrey Post, Yasmeen Al-Hindawi, Sarah Barney, Anthony Byrne, Lee Mead, Marshall Plit, David Lynn, Saoirse Benson, Stephen Blake, Rochelle Botten, Tee Yee Chern, Georgina Eden, Liddy Griffith, Jane James, Miriam Lynn, Angela Markow, Domenic Sacca, Natalie Stevens, Steve Wesselingh, Catriona Doran, Alice Sawka, Sue Evans, Louise Goodchild, Christine Heath, Meredith Krieg, Helen Marshall, Mark McMillan, Mary Walker, Peter Richmond, Nelly Amenyogbe, Christina Anthony, Annabelle Arnold, Beth Arrowsmith, Rym Ben-Othman, Sharon Clark, Jemma Dunnill, Nat Eiffler, Krist Ewe, Carolyn Finucane, Lorraine Flynn, Camille Gibson, Lucy Hartnell, Elysia Hollams, Heidi Hutton, Lance Jarvis, Jane Jones, Jan Jones, Karen Jones, Jennifer Kent, Tobias Kollmann, Debbie Lalich, Wenna Lee, Rachel Lim, Sonia McAlister, Fiona McDonald, Andrea Meehan, Asma Minhaj, Lisa Montgomery, Melissa O'Donnell, Jaslyn Ong, Joanne Ong, Kimberley Parkin, Glady Perez, Catherine Power, Shadie Rezazadeh, Holly Richmond, Sally Rogers, Nikki Schultz, Margaret Shave, Patrycja Skut, Lisa Stiglmayer, Alexandra Truelove, Ushma Wadia, Rachael Wallace, Justin Waring, Michelle England, Erin Latkovic, Susan Herrmann, Marcus Lacerda, Paulo Henrique Andrade, Fabiane Bianca Barbosa, Dayanne Barros, Larissa Brasil, Ana Greyce Capella, Ramon Castro, Erlane Costa, Dilcimar de Souza, Maianne Dias, José Dias, Klenilson Ferreira, Paula Figueiredo, Thamires Freitas, Ana Carolina Furtado, Larissa Gama, Vanessa Godinho, Cintia Gouy, Daniele Hinojosa, Tyane Jardim, Joel Junior, Augustto Lima, Bernardo Maia, Adriana Marins, Kelry Mazurega, Tercilene Medeiros, Rosangela Melo, Marinete Moraes, Elizandra Nascimento, Juliana Neves, Maria Gabriela Oliveira, Thais Oliveira, Ingrid Oliveira, Arthur Otsuka, Rayssa Paes, Handerson Pereira, Gabrielle Pereira, Christiane Prado, Evelyn Queiroz, Laleyska Rodrigues, Bebeto Rodrigues, Vanderson Sampaio, Anna Gabriela Santos, Daniel Santos, Tilza Santos, Evelyn Santos, Ariandra Sartim, Ana Beatriz Silva, Juliana Silva, Emanuelle Silva, Mariana Simão, Caroline Soares, Antonny Sousa, Alexandre Trindade, Fernando Val, Adria Vasconcelos, Heline Vasconcelos, Carolinne Abreu, Katya Martinez Almeida, Camila Bitencourt de Andrade, Jhenyfer Thalyta Campos Angelo, Ghislaine Gonçalvez de Araújo Arcanjo, Bianca Maria Silva Menezes Arruda, Wellyngthon Espindola Ayala, Adelita Agripina Refosco Barbosa, Felipe Zampieri Vieira Batista, Fabiani de Morais Batista, Miriam de Jesus Costa, Mariana Garcia Croda, Lais Alves da Cruz, Roberta Carolina Pereira Diogo, Rodrigo Cezar Dutra Escobar, Iara Rodrigues Fernandes, Leticia Ramires Figueiredo, Leandro Galdino Cavalcanti Gonçalves, Sarita Lahdo, Joyce dos Santos Lencina, Guilherme Teodoro de Lima, Bruna Tayara LEOPOLDINA MEIRELES, Debora Quadros Moreira, Lilian Batista Silva Muranaka, Adriely de Oliveira, Karla Regina Warszawski de Oliveira, Matheus Vieira de Oliveira, Roberto Dias de Oliveira, Andrea Antonia Souza de Almeida dos Reis Pereira, Marco Puga, Caroliny Veron Ramos, Thaynara Haynara Souza da Rosa, Karla Lopes dos Santos, Claudinalva Ribeiro dos Santos, Dyenyffer Stéffany Leopoldina dos Santos, Karina Marques Santos, Paulo César Pereira da Silva, Paulo Victor Rocha da Silva, Débora dos Santos Silva, Patricia Vieira da Silva, Bruno Freitas da Rosa Soares, Mariana Gazzoni Sperotto, Mariana Mayumi Tadokoro, Daniel Tsuha, Hugo Miguel Ramos Vieira, Margareth Maria Pretti Dalcolmo, Cíntia Maria Lopes Alves da Paixão, Gabriela Corrêa E Castro, Simone Silva Collopy, Renato da Costa Silva, Samyra Almeida da Silveira, Alda Maria Da-Cruz, Alessandra Maria da Silva Passos de Carvalho, Rita de Cássia Batista, Maria Luciana Silva De Freitas, Aline Gerhardt de Oliveira Ferreira, Ana Paula Conceição de Souza, Paola Cerbino Doblas, Ayla Alcoforado da Silva dos Santos, Vanessa Cristine de Moraes dos Santos, Dayane Alves dos Santos Gomes, Anderson Lage Fortunato, Adriano Gomes-Silva, Monique Pinto Gonçalves, Paulo Leandro Garcia Meireless Junior, Estela Martins da Costa Carvalho, Fernando do Couto Motta, Ligia Maria Olivo de Mendonça, Girlene dos Santos Pandine, Rosa Maria Plácido Pereira, Ivan Ramos Maia, Jorge Luiz da Rocha, João Victor Paiva Romano, Glauce dos Santos, Erica Fernandes da Silva, Marilda Agudo Mendonça Teixeira de Siqueira, Ágatha Cristinne Prudêncio Soares, Sandra Franch Arroyo, Henny Ophorst-den Besten, Anna Boon, Karin M. Brakke, Axel Janssen, Marijke A.H. Koopmans, Toos Lemmens, Titia Leurink, Engelien Septer-Bijleveld, Kimberly Stadhouders, Darren Troeman, Marije van der Waal, Marjoleine van Opdorp, Nicolette van Sluis, Beatrijs Wolters, Jan Kluytmans, Jannie Romme, Wouter van den Bijllaardt, Linda van Mook, M.M.L (Miranda) van Rijen, P.M.G. Filius, Jet Gisolf, Frances Greven, Danique Huijbens, Robert Jan Hassing, R.C. Pon, Lieke Preijers, J.H. van Leusen, Harald Verheij, Wim Boersma, Evelien Brans, Paul Kloeg, Kitty Molenaar-Groot, Nhat Khanh Nguyen, Nienke Paternotte, Anke Rol, Lida Stooper, Helga Dijkstra, Esther Eggenhuizen, Lucas Huijs, Simone Moorlag, Mihai Netea, Eva Pranger, Esther Taks, Jaap ten Oever, Rob ter Heine, Kitty Blauwendraat, Bob Meek, Isil Erkaya, Houda Harbech, Nienke Roescher, Rifka Peeters, Menno te Riele, Carmen Zhou, Esther Calbo, Cristina Badia Marti, Emma Triviño Palomares, Tomás Perez Porcuna, Anabel Barriocanal, Ana Maria Barriocanal, Irma Casas, Jose Dominguez, Maria Esteve, Alicia Lacoma, Irene Latorre, Gemma Molina, Barbara Molina, Antoni Rosell, Sandra Vidal, Lydia Barrera, Natalia Bustos, Ines Portillo Calderón, David Gutierrez Campos, Jose Manuel Carretero, Angel Dominguez Castellano, Renato Compagnone, Encarnacion Ramirez de Arellano, Almudena de la Serna, Maria Dolores del Toro Lopez, Marie-Alix Clement Espindola, Ana Belen Martin Gutierrez, Alvaro Pascual Hernandez, Virginia Palomo Jiménez, Elisa Moreno, Nicolas Navarrete, Teresa Rodriguez Paño, Jesús Rodríguez-Baño, Enriqueta Tristán, Maria Jose Rios Villegas, Atsegiñe Canga Garces, Erika Castro Amo, Raquel Coya Guerrero, Josune Goikoetxea, Leticia Jorge, Cristina Perez, María Carmen Fariñas Álvarez, Manuel Gutierrez Cuadra, Francisco Arnaiz de las Revillas Almajano, Pilar Bohedo Garcia, Teresa Giménez Poderos, Claudia González Rico, Blanca Sanchez, Olga Valero, Noelia Vega, Anna Barnes, Helen Catterick, Tim Cranston, Phoebe Dawe, Emily Fletcher, Liam Fouracre, Alison Gifford, Neil Gow, John Kirkwood, Christopher Martin, Amy McAnew, Marcus Mitchell, Georgina Newman, Abby O'Connell, Jakob Onysk, Lynne Quinn, Shelley Rhodes, Samuel Stone, Lorrie Symons, Harry Tripp, Darcy Watkins, Bethany Whale, Alex Harding, Gemma Lockhart, Kate Sidaway-Lee, Sam Hilton, Sarah Manton, Daniel Webber-Rookes, Rachel Winder, James Moore, Freya Bateman, Michael Gibbons, Bridget Knight, Julie Moss, Sarah Statton, Josephine Studham, Lydia Hall, Will Moyle, and Tamsin Venton

Subjects
Bacille Calmette-Guérin (BCG) vaccine, Immunity, Heterologous, Health personnel, Randomised controlled trial, Primary prevention, Medicine (General), R5-920
Abstract

Summary: Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Published
2024
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2. Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trialResearch in context

Author

Laure F. Pittet, Cecilia L. Moore, Ellie McDonald, Simone Barry, Marc Bonten, John Campbell, Julio Croda, Margareth Dalcolmo, Andrew Davidson, Mark W. Douglas, Kaya Gardiner, Amanda Gwee, Bruno Jardim, Marcus V.G. Lacerda, Michaela Lucas, David J. Lynn, Laurens Manning, Roberto D. de Oliveira, Kirsten P. Perrett, Cristina Prat-Aymerich, Peter C. Richmond, Jorge L. Rocha, Jesus Rodriguez-Baño, Adilia Warris, Nicholas J. Wood, Nicole L. Messina, Nigel Curtis, Tenaya Jamieson, Nicole Messina, Thilanka Morawakage, Susan Perlen, Kirsten Perrett, Laure Pittet, Amber Sastry, Jia Wei Teo, Francesca Orsini, Katherine Lee, Cecilia Moore, Suzanna Vidmar, Rashida Ali, Ross Dunn, Peta Edler, Grace Gell, Casey Goodall, Richard Hall, Ann Krastev, Nathan La, Nick McPhate, Thao Nguyen, Jack Ren, Luke Stevens, Ahmed Alamrousi, Rhian Bonnici, Thanh Dang, Susie Germano, Jenny Hua, Rebecca McElroy, Monica Razmovska, Scott Reddiex, Xiaofang Wang, Jeremy Anderson, Kristy Azzopardi, Vicki Bennett-Wood, Anna Czajko, Nadia Mazarakis, Conor McCafferty, Frances Oppedisano, Belinda Ortika, Casey Pell, Leena Spry, Ryan Toh, Sunitha Velagapudi, Amanda Vlahos, Ashleigh Wee-Hee, Pedro Ramos, Karina De La Cruz, Dinusha Gamage, Anushka Karunanayake, Isabella Mezzetti, Benjamin Ong, Ronita Singh, Enoshini Sooriyarachchi, Suellen Nicholson, Natalie Cain, Rianne Brizuela, Han Huang, Veronica Abruzzo, Morgan Bealing, Patricia Bimboese, Kirsty Bowes, Emma Burrell, Joyce Chan, Jac Cushnahan, Hannah Elborough, Olivia Elkington, Kieran Fahey, Monique Fernandez, Catherine Flynn, Sarah Fowler, Marie Gentile Andrit, Bojana Gladanac, Catherine Hammond, Norine Ma, Sam Macalister, Emmah Milojevic, Jesutofunmi Mojeed, Jill Nguyen, Liz O'Donnell, Nadia Olivier, Isabelle Ooi, Stephanie Reynolds, Lisa Shen, Barb Sherry, Judith Spotswood, Jamie Wedderburn, Angela Younes, Donna Legge, Jason Bell, Jo Cheah, Annie Cobbledick, Kee Lim, Sonja Elia, Lynne Addlem, Anna Bourke, Clare Brophy, Nadine Henare, Narelle Jenkins, Francesca Machingaifa, Skye Miller, Kirsten Mitchell, Sigrid Pitkin, Kate Wall, Paola Villanueva, Nigel Crawford, Wendy Norton, Niki Tan, Thilakavathi Chengodu, Diane Dawson, Victoria Gordon, Tony Korman, Jess O'Bryan, Sophie Agius, Samantha Bannister, Jess Bucholc, Alison Burns, Beatriz Camesella, John Carlin, Marianna Ciaverella, Maxwell Curtis, Stephanie Firth, Christina Guo, Matthew Hannan, Erin Hill, Sri Joshi, Katherine Lieschke, Megan Mathers, Sasha Odoi, Ashleigh Rak, Chris Richards, Leah Steve, Carolyn Stewart, Eva Sudbury, Helen Thomson, Emma Watts, Fiona Williams, Angela Young, Penny Glenn, Andrew Kaynes, Amandine Philippart De Floy, Sandy Buchanan, Thijs Sondag, Ivy Xie, Harriet Edmund, Bridie Byrne, Tom Keeble, Belle Ngien, Fran Noonan, Michelle Wearing-Smith, Alison Clarke, Pemma Davies, Oliver Eastwood, Alric Ellinghaus, Rachid Ghieh, Zahra Hilton, Emma Jennings, Athina Kakkos, Iris Liang, Katie Nicol, Sally O'Callaghan, Helen Osman, Gowri Rajaram, Sophia Ratcliffe, Victoria Rayner, Ashleigh Salmon, Angela Scheppokat, Aimee Stevens, Rebekah Street, Nicholas Toogood, Nicholas Wood, Twinkle Bahaduri, Therese Baulman, Jennifer Byrne, Candace Carter, Mary Corbett, Aiken Dao, Maria Desylva, Andrew Dunn, Evangeline Gardiner, Rosemary Joyce, Rama Kandasamy, Craig Munns, Lisa Pelayo, Ketaki Sharma, Katrina Sterling, Caitlin Uren, Clinton Colaco, Mark Douglas, Kate Hamilton, Adam Bartlett, Brendan McMullan, Pamela Palasanthiran, Phoebe Williams, Justin Beardsley, Nikki Bergant, Renier Lagunday, Kristen Overton, Jeffrey Post, Yasmeen Al-Hindawi, Sarah Barney, Anthony Byrne, Lee Mead, Marshall Plit, David Lynn, Saoirse Benson, Stephen Blake, Rochelle Botten, Tee Yee Chern, Georgina Eden, Liddy Griffith, Jane James, Miriam Lynn, Angela Markow, Domenic Sacca, Natalie Stevens, Steve Wesselingh, Catriona Doran, Alice Sawka, Sue Evans, Louise Goodchild, Christine Heath, Meredith Krieg, Helen Marshall, Mark McMillan, Mary Walker, Peter Richmond, Nelly Amenyogbe, Christina Anthony, Annabelle Arnold, Beth Arrowsmith, Rym Ben-Othman, Sharon Clark, Jemma Dunnill, Nat Eiffler, Krist Ewe, Carolyn Finucane, Lorraine Flynn, Camille Gibson, Lucy Hartnell, Elysia Hollams, Heidi Hutton, Lance Jarvis, Jane Jones, Jan Jones, Karen Jones, Jennifer Kent, Tobias Kollmann, Debbie Lalich, Wenna Lee, Rachel Lim, Sonia McAlister, Fiona McDonald, Andrea Meehan, Asma Minhaj, Lisa Montgomery, Melissa O'Donnell, Jaslyn Ong, Joanne Ong, Kimberley Parkin, Glady Perez, Catherine Power, Shadie Rezazadeh, Holly Richmond, Sally Rogers, Nikki Schultz, Margaret Shave, Patrycja Skut, Lisa Stiglmayer, Alexandra Truelove, Ushma Wadia, Rachael Wallace, Justin Waring, Michelle England, Erin Latkovic, Susan Herrmann, Marcus Lacerda, Paulo Henrique Andrade, Fabiane Bianca Barbosa, Dayanne Barros, Larissa Brasil, Ana Greyce Capella, Ramon Castro, Erlane Costa, Dilcimar de Souza, Maianne Dias, José Dias, Klenilson Ferreira, Paula Figueiredo, Thamires Freitas, Ana Carolina Furtado, Larissa Gama, Vanessa Godinho, Cintia Gouy, Daniele Hinojosa, Tyane Jardim, Joel Junior, Augustto Lima, Bernardo Maia, Adriana Marins, Kelry Mazurega, Tercilene Medeiros, Rosangela Melo, Marinete Moraes, Elizandra Nascimento, Juliana Neves, Maria Gabriela Oliveira, Thais Oliveira, Ingrid Oliveira, Arthur Otsuka, Rayssa Paes, Handerson Pereira, Gabrielle Pereira, Christiane Prado, Evelyn Queiroz, Laleyska Rodrigues, Bebeto Rodrigues, Vanderson Sampaio, Anna Gabriela Santos, Daniel Santos, Tilza Santos, Evelyn Santos, Ariandra Sartim, Ana Beatriz Silva, Juliana Silva, Emanuelle Silva, Mariana Simão, Caroline Soares, Antonny Sousa, Alexandre Trindade, Fernando Val, Adria Vasconcelos, Heline Vasconcelos, Carolinne Abreu, Katya Martinez Almeida, Camila Bitencourt de Andrade, Jhenyfer Thalyta Campos Angelo, Ghislaine Gonçalvez de Araújo Arcanjo, Bianca Maria Silva Menezes Arruda, Wellyngthon Espindola Ayala, Adelita Agripina Refosco Barbosa, Felipe Zampieri Vieira Batista, Fabiani de Morais Batista, Miriam de Jesus Costa, Mariana Garcia Croda, Lais Alves da Cruz, Roberta Carolina Pereira Diogo, Rodrigo Cezar Dutra Escobar, Iara Rodrigues Fernandes, Leticia Ramires Figueiredo, Leandro Galdino Cavalcanti Gonçalves, Sarita Lahdo, Joyce dos Santos Lencina, Guilherme Teodoro de Lima, Larissa Santos Matos, Bruna Tayara Leopoldina Meireles, Debora Quadros Moreira, Lilian Batista Silva Muranaka, Adriely de Oliveira, Karla Regina Warszawski de Oliveira, Matheus Vieira de Oliveira, Roberto Dias de Oliveira, Andrea Antonia Souza de Almeida dos Reis Pereira, Marco Puga, Caroliny Veron Ramos, Thaynara Haynara Souza da Rosa, Karla Lopes dos Santos, Claudinalva Ribeiro dos Santos, Dyenyffer Stéffany Leopoldina dos Santos, Karina Marques Santos, Paulo César Pereira da Silva, Paulo Victor Rocha da Silva, Débora dos Santos Silva, Patricia Vieira da Silva, Bruno Freitas da Rosa Soares, Mariana Gazzoni Sperotto, Mariana Mayumi Tadokoro, Daniel Tsuha, Hugo Miguel Ramos Vieira, Margareth Maria Pretti Dalcolmo, Cíntia Maria Lopes Alves da Paixão, Gabriela Corrêa E Castro, Simone Silva Collopy, Renato da Costa Silva, Samyra Almeida da Silveira, Alda Maria Da-Cruz, Alessandra Maria da Silva Passos de Carvalho, Rita de Cássia Batista, Maria Luciana Silva De Freitas, Aline Gerhardt de Oliveira Ferreira, Ana Paula Conceição de Souza, Paola Cerbino Doblas, Ayla Alcoforado da Silva dos Santos, Vanessa Cristine de Moraes dos Santos, Dayane Alves dos Santos Gomes, Anderson Lage Fortunato, Adriano Gomes-Silva, Monique Pinto Gonçalves, Paulo Leandro Garcia Meireless Junior, Estela Martins da Costa Carvalho, Fernando do Couto Motta, Ligia Maria Olivo de Mendonça, Girlene dos Santos Pandine, Rosa Maria Plácido Pereira, Ivan Ramos Maia, Jorge Luiz da Rocha, João Victor Paiva Romano, Glauce dos Santos, Erica Fernandes da Silva, Marilda Agudo Mendonça Teixeira de Siqueira, Ágatha Cristinne Prudêncio Soares, Sandra Franch Arroyo, Henny Ophorst-den Besten, Anna Boon, Karin M. Brakke, Axel Janssen, Marijke A.H. Koopmans, Toos Lemmens, Titia Leurink, Engelien Septer-Bijleveld, Kimberly Stadhouders, Darren Troeman, Marije van der Waal, Marjoleine van Opdorp, Nicolette van Sluis, Beatrijs Wolters, Jan Kluytmans, Jannie Romme, Wouter van den Bijllaardt, Linda van Mook, M.M.L (Miranda) van Rijen, P.M.G. Filius, Jet Gisolf, Frances Greven, Danique Huijbens, Robert Jan Hassing, R.C. Pon, Lieke Preijers, J.H. van Leusen, Harald Verheij, Wim Boersma, Evelien Brans, Paul Kloeg, Kitty Molenaar-Groot, Nhat Khanh Nguyen, Nienke Paternotte, Anke Rol, Lida Stooper, Helga Dijkstra, Esther Eggenhuizen, Lucas Huijs, Simone Moorlag, Mihai Netea, Eva Pranger, Esther Taks, Jaap ten Oever, Rob ter Heine, Kitty Blauwendraat, Bob Meek, Isil Erkaya, Houda Harbech, Nienke Roescher, Rifka Peeters, Menno te Riele, Carmen Zhou, Esther Calbo, Cristina Badia Marti, Emma Triviño Palomares, Tomás Perez Porcuna, Anabel Barriocanal, Ana Maria Barriocanal, Irma Casas, Jose Dominguez, Maria Esteve, Alicia Lacoma, Irene Latorre, Gemma Molina, Barbara Molina, Antoni Rosell, Sandra Vidal, Lydia Barrera, Natalia Bustos, Ines Portillo Calderón, David Gutierrez Campos, Jose Manuel Carretero, Angel Dominguez Castellano, Renato Compagnone, Encarnacion Ramirez de Arellano, Almudena de la Serna, Maria Dolores del Toro Lopez, Marie-Alix Clement Espindola, Ana Belen Martin Gutierrez, Alvaro Pascual Hernandez, Virginia Palomo Jiménez, Elisa Moreno, Nicolas Navarrete, Teresa Rodriguez Paño, Jesús Rodríguez-Baño, Enriqueta Tristán, Maria Jose Rios Villegas, Atsegiñe Canga Garces, Erika Castro Amo, Raquel Coya Guerrero, Josune Goikoetxea, Leticia Jorge, Cristina Perez, María Carmen Fariñas Álvarez, Manuel Gutierrez Cuadra, Francisco Arnaiz de las Revillas Almajano, Pilar Bohedo Garcia, Teresa Giménez Poderos, Claudia González Rico, Blanca Sanchez, Olga Valero, Noelia Vega, Anna Barnes, Helen Catterick, Tim Cranston, Phoebe Dawe, Emily Fletcher, Liam Fouracre, Alison Gifford, John Kirkwood, Christopher Martin, Amy McAnew, Marcus Mitchell, Georgina Newman, Abby O'Connell, Jakob Onysk, Lynne Quinn, Shelley Rhodes, Samuel Stone, Lorrie Symons, Harry Tripp, Darcy Watkins, Bethany Whale, Alex Harding, Gemma Lockhart, Kate Sidaway-Lee, Sam Hilton, Sarah Manton, Daniel Webber-Rookes, Rachel Winder, James Moore, Freya Bateman, Michael Gibbons, Bridget Knight, Julie Moss, Sarah Statton, Josephine Studham, Lydia Hall, Will Moyle, and Tamsin Venton

Subjects
Herpes simplex virus, Cold sore, Herpes labialis, Bacille Calmette-Guérin, Mycobacterium bovis, Prevention, Medicine (General), R5-920
Abstract

Summary: Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

Published
2023
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3. The Effects Of Protease-Activated Receptors 1 And 4 In Human Platelet Activation And Inflammation

Author

Jianying Zhang PhD, Jorge L. Rocha BA, Justin H. Hicks Biomedical Engineering, Melissa McLane, James H-C. Wang PhD, and MaCalus V. Hogan MD

Subjects
Orthopedic surgery, RD701-811
Abstract

Category: Basic Sciences/Biologics Introduction/Purpose: Tendon injuries occur frequently and cost billions of health care dollars annually. Recently, there has been an increase in the use of platelet-rich plasma (PRP) to treat tendon injuries. However, the efficacy of PRP treatment is controversial due to inconsistent results from human clinical trials. It is thought that variations in PRP preparation contribute to these inconsistencies. Specifically, platelets in PRP contain pro-angiogenic (e.g. VEGF) or anti-angiogenic (e.g. endostatin) factors, which may differentially affect the healing of tendon injuries. It is known that these factors are selectively released after platelet activation by specific receptors. Therefore, in this study we investigated the effect of protease-activated receptors 1 and 4 (PAR1 and PAR4) in platelet activation and inflammation. Methods: Platelet preparation – Human blood was obtained from 12 healthy donors and 9 ml of blood was mixed with 1 ml of 3.8% sodium citrate and centrifuged at 500g for 10 min. Then, the supernatant (PRP) without the buffy coat was centrifuged at 1000g for 10 min and the resulting pellet was washed in Tyrodes-HEPES buffer and centrifuged for 10 min at 1000g. Finally, platelets in the pellet was suspended in Tyrodes-HEPES buffer and used in experiments. Platelet activation – About 100 μl of platelet from above was activated with 5 μl 1 mM PAR1-activating peptide (PAR1-AP) or PAR4-activating peptide (PAR4-AP) at 25°C for 10 min. Then, the mixture was centrifuged at 1000g for 10 min, and the levels of VEGF, endostatin, IL-1RA and HMGB-1in the supernatant was determined by ELISA. Platelets without activators were used as controls. Results: PAR1 induced angiogenic effects in human platelets. PAR1 activated platelets released 3 times more VEGF than when activated with PAR4 (Fig. 1A). However, PAR4 activated platelets released 7 times more endostatin than the PAR1 activated platelets (Fig. 1B). Further, PAR1 induced anti-inflammatory effects in human platelets; it did not change IL-1R-A (Fig. 2A) but decreased HMGB-1 levels (Fig. 2B). In contrast, PAR4 stimulated inflammatory effects in human platelets by lowering IL-1-RA and increasing HMGB-1 levels. Conclusion: Our findings indicate that PAR1 induces angiogenetic and anti-inflammatory effects in human platelets, while PAR4 has anti-angiogenetic and inflammatory effects. Of significance is HMGB-1, which is constitutively expressed in the nuclei of most mammalian cells. Under cellular stress, HMGB1 is released into the extracellular matrix and activates the immune response thus acting as a danger-signal. Both PAR1 and PAR4 selectively regulated the release of VEGF and endostatin, and IL-1RA and HMGB-1 from human platelets. Therefore, the role of PAR1 and PAR4 on human platelet activation and inflammation should be considered prior to the use of PRP to treat tendon injuries.

Published
2016
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4. Sustained Release of Bone Morphogenetic Protein 2 via Coacervate

Author

MaCalus V. Hogan MD, Justin H. Hicks, Biomedical Engineering, Jorge L. Rocha BA, Hongshuai Li MD, PhD, Yadong Wang, and Johnny Huard

Subjects
Orthopedic surgery, RD701-811
Abstract

Category: Basic Sciences/Biologics Introduction/Purpose: Currently, there is no cure for osteoarthritis (OA) with treatment aimed at symptom relief and improved function. Muscle-derived stem cells (MDSCs) have been shown to exhibit long-term proliferation, high self-renewal, and can undergo chondrogenic differentiation when cultivated in chondrogenic medium in vitro and can differentiate into chondrocytes and repair injured articular cartilage (AC) in vivo. MDSCs retrovirally transduce to express chondrogenic proteins (BMPs) to differentiate into chondrocytes and enhance cartilage repair in vivo. Gene therapy is a promising approach to promote the chondrogenic potentials of MDSCs for AC repair. We have developed a unique sustained growth factor delivery platform comprised of native heparin and a synthetic polycation incorporated with BMP2 (BMP2 coacervate) which can sustain delivery of BMPs to stimulate the chondrogenesis of MDSCs for AC repair. Methods: MDSC were stimulated in vitro with single dose of free BMP2, multi-dose BMP2, BMP2 coacervate, coacervate alone (vehicle only), or in the absence of BMP2 and coacervate (control). BMP2 effects on MDSCs were evaluated by RT-PCR. 20μl of a MIA solution was injected into the knee joint of C57B6 mice to induce osteoarthritic lesions. Two weeks after MIA injection, 20μl of PBS (PBS control), 1×106 MDSCs with 1μg of free BMP2 (MDSC-free BMP), or MDSCs with 1μg BMP2-coacervate (MDSC- BMP coacervate) were injected into the knee joints of the OA injured mice. After 4 weeks, macroscopic and histologic evaluations of cartilage regeneration were conducted. Results: mRNA expression of Aggrecan and Col2A were significantly higher in each BMP2 group compared to control or vehicle only (P < 0.05). Multi-dosage free BMP2 demonstrated significantly higher Aggrecan expression compared to single dose free BMP2 (p < 0.05). Col2A and aggrecan expression in the BMP coacervate group was superior to both single and mult-dose free BMP2 delivery (p < 0.05) (Fig 1A). Histologic examination demonstrated superior cartilage repair and integration in the BMP2 coacervate group (Fig. 1B). Conclusion: This study demonstrates that sustained growth factor delivery (BMP2) is a potential therapeutic option for muscle- derived stem cell based cartilage regeneration for the treatment of osteoarthritis. Prolonged delivery of BMP2 via coacervate led to enhanced MDSC chondrogenesis in vivo and improved cartilage regeneration in vivo. Our results demonstrate an effective method for prolonged exposure to BMP2 and is more clinically translatable.

Published
2016
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5. Hemisferectomía: experiencia institucional y revisión sistemática de la literatura

Author

Marco T. Dorado, Loida Camargo, Karen Sofia Tejada, Jorge L. Rocha, Mauro M. Suárez, Jaime Fandiño, and Kevin de León

Subjects
03 medical and health sciences, 0302 clinical medicine, Neurology, 030220 oncology & carcinogenesis, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

Resumen Objetivos La hemisferectomia es considerada una opcion terapeutica en el tratamiento de ninos y adultos con epilepsia refractaria que presentan un dano unilateral y hemisferico importante. El objetivo de esta serie de casos es realizar una descripcion de la poblacion tratada con epilepsia refractaria en el FIRE entre los anos 1986 y 2014 a quienes se les practico una hemisferectomia. Metodos Se realizo un estudio retrospectivo de casos tomados de la base de datos de historias clinicas de los pacientes sometidos a hemisferectomia desde el ano 1986 hasta el ano 2014 de la institucion. Ademas se realizo una busqueda sistematica de la literatura en las bases de datos PubMed y SciELO. Resultados Se describen 53 sujetos sometidos a hemisferectomia, con edades comprendidas entre 0 y 43 anos en el momento de la cirugia. En la mayoria de los pacientes la causa de la epilepsia fue secundaria a malformaciones del desarrollo cortical (71,6%). En el momento de las valoraciones posquirurgicas, 29 pacientes se encontraron en la categoria i de Engel. Las complicaciones postoperatorias fueron pocas, siendo vasculares las mas frecuentes, con el 5,6% de los casos, seguidas de las infecciosas. Conclusiones La hemisferectomia es una tecnica confiable y efectiva para el manejo de pacientes pediatricos y adultos con epilepsia refractaria que presentan dano hemisferico cerebral. Los resultados postoperatorios demuestran una baja morbimortalidad en pacientes seleccionados. Nuestros datos evidencian efectos positivos en la evolucion postoperatoria en cuanto al control de las crisis epilepticas.

Published
2020

6. Reverse Total Shoulder Arthroplasty for Geriatric Proximal Humerus Fracture Dislocation With Concomitant Nerve Injury

Author

Daiji Kano, Gregory Gasbarro, Ivan S. Tarkin, Sarah Henry, Jorge L. Rocha, and Jared A. Crasto

Subjects
medicine.medical_specialty, medicine.medical_treatment, proximal humerus, lcsh:Geriatrics, 03 medical and health sciences, 0302 clinical medicine, lcsh:Orthopedic surgery, medicine, Orthopedics and Sports Medicine, 030212 general & internal medicine, Contraindication, brachial plexus, 030222 orthopedics, business.industry, fracture-dislocations, Rehabilitation, Axillary nerve palsy, Nerve injury, medicine.disease, Arthroplasty, Surgery, axillary nerve, lcsh:RD701-811, lcsh:RC952-954.6, Concomitant, reverse total shoulder arthroplasty, deltoid palsy, Original Article, nerve injury, Axillary nerve, Geriatrics and Gerontology, Dislocation, medicine.symptom, business, Brachial plexus
Abstract

Introduction: Preoperative axillary nerve palsy is a contraindication to reverse total shoulder arthroplasty (rTSA) due to the theoretical risk of higher dislocation rates and poor functional outcomes. Treatment of fracture-dislocations of the proximal humerus with rTSA is particularly challenging, as these injuries commonly present with concomitant neurologic and soft tissue injury. The aim of the current study was to determine the efficacy of rTSA for this fracture pattern in geriatric patients presenting with occult or profound neurologic injury. Methods: A retrospective case series of all shoulder arthroplasty procedures for proximal humerus fractures from February 2006 to February 2018 was performed. Inclusion criteria were patients aged greater than 65 years at the time of surgery, fracture-dislocations of the proximal humerus, and treatment with rTSA. Patients with preoperative nerve injuries were compared to patients without overt neurologic dysfunction. Forward elevation, Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH), Visual Analog Scale (VAS), and Subjective Shoulder Value (SSV) were obtained at final follow-up. Results: Forty-six rTSA for acute fracture were performed during the study period, 16 patients met the inclusion criteria and 5 (31%) presented with overt preoperative nerve injuries. At mean 3.1 years follow up, there were no postoperative complications including dislocations and final forward elevation was similar between study groups. Patients with overt nerve palsy had higher QuickDASH and VAS scores with lower SSV and self-rated satisfaction. Discussion: In the majority of patients with or without overt nerve injury, rTSA reliably restored overhead function and led to good or excellent patient-rated treatment outcomes. Overt nerve palsy did not lead to higher complication rates, including dislocation. Despite greater disability and less satisfaction, complete or partial nerve recovery can be expected in the majority of patients. Conclusion: Nerve injury following proximal humeral fracture dislocation may not be an absolute contraindication to rTSA.

Published
2019

7. Lisfranc Complex Injuries

Author

Lorraine A. T. Boakye, Stephanie M. Jones, Arthur R. McDowell, MaCalus V. Hogan, Samuel O. Ewalefo, Humza Shaik, Scott Nimmons, and Jorge L. Rocha

Subjects
Tarsometatarsal joints, Lisfranc injury, medicine.medical_specialty, business.industry, medicine.medical_treatment, Arthrodesis, Context (language use), Osteoarthritis, Articular cartilage damage, medicine.disease, Surgery, medicine.anatomical_structure, medicine, Internal fixation, business, Reduction (orthopedic surgery)
Abstract

Lisfranc or tarsometatarsal joint complex injuries are rare and often missed or misdiagnosed. Delayed diagnosis of Lisfranc injuries may result in significant long-term morbidity. The most common mechanism of Lisfranc injury is forceful axial loading of the plantarflexed foot. The tarsometatarsal joint complex provides significant structural support for the transverse arch of the midfoot. Dorsal, interosseous, and plantar ligaments, collectively known as the “Lisfranc ligament,” stabilize the articulation between the medial cuneiform and the second metatarsal base. However, Lisfranc injuries may involve any of the tarsometatarsal joints within the complex. Tarsometatarsal joint complex injuries may be associated with articular cartilage damage sustained at the time of injury and often pose a high risk for post-traumatic osteoarthritis and chronic pain. Management of Lisfranc injuries is tailored to the acuity, pattern, and severity of the injury within the context of patient-specific demographic factors. Non-operative management is typically recommended for stable injuries, while unstable injuries are often treated via surgical intervention. Surgical stabilization of the Lisfranc joint is most commonly achieved with either open reduction and internal fixation or primary arthrodesis of the associated joints. Anatomic reduction of the tarsometatarsal joint complex is a key factor in determining positive outcomes following injury; and as such, operative management for Lisfranc injuries has proven to be a superior treatment option when compared to non-operative management.

Published
2019

8. Selectively activated PRP exerts differential effects on tendon stem/progenitor cells and tendon healing

Author

Jorge L. Rocha, Kelly Williamson, Daibang Nie, Jianying Zhang, MaCalus V. Hogan, and James H.-C. Wang

Subjects
Pathology, medicine.medical_specialty, PRP, animal diseases, Biomedical Engineering, Medicine (miscellaneous), Matrix (biology), Biomaterials, lcsh:Biochemistry, 03 medical and health sciences, 0302 clinical medicine, medicine, lcsh:QD415-436, Progenitor cell, Receptor, Tendon healing, 030304 developmental biology, 0303 health sciences, TSCs, Chemistry, PAR4, healing, musculoskeletal system, Differential effects, PAR1, 3. Good health, Tendon, nervous system diseases, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Platelet-rich plasma, cardiovascular system, Original Article, Endostatin
Abstract

To understand the variable efficacy with platelet rich plasma (PRP) treatments for tendon injury, we determined the differential effects of proteinase-activated receptor (PAR)1- or PAR4-activated PRP (PAR1-PRP, PAR4-PRP) from humans on human patellar tendon stem/progenitor cells (TSCs) and tendon healing. We show that PAR1-PRP released VEGF, whereas PAR4-PRP released endostatin. Treatment of TSCs with PAR1-PRP increased collagen I expression and matrix metalloproteinase-1 (MMP-1), but cells treated with PAR4-PRP increased less collagen I and higher MMP-2 expression. The wound area treated with PAR4-PRP formed tendon-like tissues with well-organized collagen fibers and fewer blood vessels, while PAR1-PRP treatment resulted in the formation of blood vessels and unhealed tissues. These findings indicate that differential activation of PRP leads to different effects on TSCs and tendon healing. We suggest that based on acute or chronic type of tendon injury, selective activation of PRP should be applied in clinics in order to treat injured tendons successfully.

Published
2019

9. Developing Performance and Assessment Platforms in Foot and Ankle Surgery

Author

Shepard R. Hurwitz, MaCalus V. Hogan, Chad Michael Ferguson, Trapper Lalli, Jorge L. Rocha, and James J. Irrgang

Subjects
030222 orthopedics, medicine.medical_specialty, Foot, business.industry, Foot and ankle surgery, Surgery, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Physical medicine and rehabilitation, medicine, Humans, Orthopedic Procedures, Orthopedics and Sports Medicine, 030212 general & internal medicine, Ankle, business, Foot (unit)
Published
2016

10. Management of Posttraumatic Ankle Arthritis: Literature Review

Author

Alex J. Kline, MaCalus V. Hogan, Jorge L. Rocha, Takashi Hirase, Samuel O. Ewalefo, Dwayne Carney, Malcolm E. Dombrowski, and Mitchell Weaver

Subjects
030222 orthopedics, medicine.medical_specialty, Allograft transplantation, Sports medicine, business.industry, Arthritis, Ankle arthritis, 030229 sport sciences, Osteoarthritis, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Orthopedic surgery, medicine, Physical therapy, Orthopedics and Sports Medicine, Ankle, Complication, business, Foot and Ankle Trauma (G Moloney, section editor)
Abstract

Trauma is the principle cause of osteoarthritis in the ankle, which is associated with significant morbidity. This review highlights the current literature for the purpose of bringing the reader up-to-date on the management of posttraumatic ankle arthritis, describing treatment efficacy, indications, contraindications, and complications. Recent studies on osteoarthritis have demonstrated variability among anatomic locations regarding the mechanisms and rates of development for posttraumatic osteoarthritis, which are attributed to newly discovered biological differences intrinsic to each joint. Regarding surgical management of posttraumatic ankle arthritis, osteochondral allograft transplantation of the talus, and supramalleolar osteotomies have demonstrated promising results. Additionally, the outpatient setting was found to be appropriate for managing pain following total ankle arthroplasty, associated with low complication rates and no readmission. Management for posttraumatic ankle arthritis is generally progressive. Initial treatment entails nonpharmacologic options with surgery reserved for posttraumatic ankle arthritis refractory to conservative treatment. Patient demographics and lifestyles should be carefully considered when formulating a management strategy, as outcomes are dependent upon the satisfaction of each set of respective criteria. Ultimately, the management of posttraumatic ankle arthritis should be individualized to satisfy the needs and desires, which are specific to each patient.

Published
2018

11. Characterization of the structure, cells, and cellular mechanobiological response of human plantar fascia

Author

Daibang Nie, Jorge L. Rocha, Jianying Zhang, MaCalus V. Hogan, and James H.-C. Wang

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Biomedical Engineering, Medicine (miscellaneous), Plantar fasciitis, Plantar fascia, Inflammation, Matrix (biology), Biology, lcsh:Biochemistry, Biomaterials, 03 medical and health sciences, Mechanobiology, 0302 clinical medicine, Tissue engineering, stem cells, medicine, lcsh:QD415-436, Progenitor cell, differentiation, 030229 sport sciences, mechanobiology, musculoskeletal system, body regions, 030104 developmental biology, medicine.anatomical_structure, inflammation, Original Article, Stem cell, medicine.symptom, human activities
Abstract

In this study, we report that human plantar fascia consists of two distinct tissues with differential structural properties. These tissues also contain stem/progenitor cells with differential biological properties. The mechanobiological responses of these two plantar fascia stem cells also differ in terms of expression of collagen I and IV, non-ligament-related genes, and proinflammatory genes. The production of inflammatory agents (prostaglandin E2, interleukin-6) and matrix degradative enzymes (matrix metalloproteinase-1, matrix metalloproteinase-2) are also different between the two types of plantar fascia stem cells. Based on the findings from this study, we suggest that plantar fasciitis results from the aberrant mechanobiological responses of the stem cells from plantar fascia sheath and core tissues. Our findings may also be used to devise tissue engineering approaches to treat plantar fascia injury effectively.

Published
2018
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12. Management of Complex Acetabular Revision With Bone Loss

Author

Michael J. O'Malley and Jorge L. Rocha

Subjects
musculoskeletal diseases, 030222 orthopedics, medicine.medical_specialty, Revision arthroplasty, business.industry, 030229 sport sciences, equipment and supplies, musculoskeletal system, Surgery, 03 medical and health sciences, 0302 clinical medicine, Acetabular bone, medicine, Treatment strategy, Orthopedics and Sports Medicine, business
Abstract

The management of acetabular bone loss during revision arthroplasty can be a difficult challenge. There is a wide variety of potential defects, as well as numerous implants and treatment strategies available to manage the problem. The assessment of the severity and location of bone loss preoperatively is imperative as remaining acetabular bone stock drives reconstruction options. This paper will describe the preoperative assessment, the acetabular defect classifications, proposed treatment algorithms, and the surgical options available to achieve a successful outcome when managing acetabular bone loss in revision arthroplasty.

Published
2019

13. Sustained Release of Bone Morphogenetic Protein 2 via Coacervate improves Muscle Derived Stem Cell Mediated Cartilage Regeneration in MIA-induced Osteoarthritis

Author

Justin James Hicks, Jorge L. Rocha, Yadong Wang, Hongshuai Li, MaCalus V. Hogan, and Johnny Huard

Subjects
0301 basic medicine, medicine.medical_specialty, Coacervate, animal structures, business.industry, Regeneration (biology), Cartilage, Degeneration (medical), Osteoarthritis, medicine.disease, Bone morphogenetic protein 2, Cell mediated immunity, Article, Surgery, 03 medical and health sciences, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Increased risk, Internal medicine, embryonic structures, medicine, Orthopedics and Sports Medicine, business
Abstract

Objectives: Individuals who participate in sports have an increased risk of osteoarthritis (OA), characterized by articular cartilage degeneration. Currently, there is no cure for OA with treatment aimed at symptom relief and improved function. Muscle-derived stem cells (MDSCs) have been shown to exhibit long-term proliferation, high self-renewal, and multipotent differentiation capabilities in vitro. Previously, we have demonstrated that murine MDSCs retrovirally transduced to express chondrogenic proteins (BMPs) differentiate into chondrocytes and enhance cartilage repair in vivo. Direct injection of therapeutic proteins can promote cartilage healing; however, they have relatively short half-lives requiring muitiple injections of high dosages. This presents a challenge in terms of maintaining adequate local BMP levels and could negatively affect both injured and normal structures and lead to side effects such as osteophyte formation. Gene therapy is a promising approach that addresses this problem; however, its utilization in clinical applications is much further down the road. In order to circumvent viral transduction of cells for cartilage regeneration, we developed a unique growth factor delivery platform comprised of native heparin and a synthetic polycation, poly(ethylene argininylaspartate diglyceride) (PEAD) incorporated with BMP2 (BMP2 coacervate). In this study, we show that sustained delivery of BMP2 via a BMP2 coacervate can induce the differentiation of MDSCs to a chondrocyte lineage for in vivo cartilage regeneration and healing in a Monoiodoacetate (MIA)-induced osteoarthritis model. Methods: mMDSCs were isolated from muscle biopsies via a modified pre-plated technique. The BMP2 coacervates were prepared as previously described. The release profiles of BMP2 coacervate were tested by ELISA. The chondrogenic effects that delivery of BMP2 had on MDSCs were evaluated by RT-PCR. The efficacy of MDSC with BMP2 coacervate were evaluated in vivo in a MIA-induced OA model in C57B6 mice. Mice received an intraarticular injection of 20μl of MIA to induce osteoarthritic lesions. Two weeks after MIA injection, mice were injected with PBS (control), MDSC + free BMP2, or MDSC + BMP2 coacervate. Histologic evaluations of cartilage regeneration were conducted at week 4. Institutional Animal Care and Use Committee approval was obtained prior to all animal studies. Results: Release profiles of BMP2 showed sustained release for more than 28 days demonstrating sustained release. The chondrogenic differentiation of MDSCs following BMP2 delivery was assayed using cell culture. The mRNA expression of Aggrecan and Col2A were significantly higher in each BMP2 group compared to control or vehicle only (PConclusion: This study demonstrates that sustained growth factor delivery (BMP2) is a potential therapeutic option for muscle-derived stem cell based cartilage regeneration for the treatment of osteoarthritis. Our results demonstrate an effective method for prolonged exposure to BMP2 via a non-gene therapy approach which is preferred and clinically translatable.

Published
2016

14. The Effects Of Protease-Activated Receptors 1 And 4 In Human Platelet Activation And Inflammation

Author

Justin H. Hicks, Jorge L. Rocha, MaCalus V. Hogan, James H.-C. Wang, Melissa McLane, and Jianying Zhang

Subjects
Protease, business.industry, medicine.medical_treatment, Inflammation, Human platelet, Pharmacology, Tendon, lcsh:RD701-811, medicine.anatomical_structure, lcsh:Orthopedic surgery, cardiovascular system, Medicine, Platelet, medicine.symptom, Endostatin, business, Receptor, Platelet factor 4
Abstract

Category: Basic Sciences/Biologics Introduction/Purpose: Tendon injuries occur frequently and cost billions of health care dollars annually. Recently, there has been an increase in the use of platelet-rich plasma (PRP) to treat tendon injuries. However, the efficacy of PRP treatment is controversial due to inconsistent results from human clinical trials. It is thought that variations in PRP preparation contribute to these inconsistencies. Specifically, platelets in PRP contain pro-angiogenic (e.g. VEGF) or anti-angiogenic (e.g. endostatin) factors, which may differentially affect the healing of tendon injuries. It is known that these factors are selectively released after platelet activation by specific receptors. Therefore, in this study we investigated the effect of protease-activated receptors 1 and 4 (PAR1 and PAR4) in platelet activation and inflammation. Methods: Platelet preparation – Human blood was obtained from 12 healthy donors and 9 ml of blood was mixed with 1 ml of 3.8% sodium citrate and centrifuged at 500g for 10 min. Then, the supernatant (PRP) without the buffy coat was centrifuged at 1000g for 10 min and the resulting pellet was washed in Tyrodes-HEPES buffer and centrifuged for 10 min at 1000g. Finally, platelets in the pellet was suspended in Tyrodes-HEPES buffer and used in experiments. Platelet activation – About 100 μl of platelet from above was activated with 5 μl 1 mM PAR1-activating peptide (PAR1-AP) or PAR4-activating peptide (PAR4-AP) at 25°C for 10 min. Then, the mixture was centrifuged at 1000g for 10 min, and the levels of VEGF, endostatin, IL-1RA and HMGB-1in the supernatant was determined by ELISA. Platelets without activators were used as controls. Results: PAR1 induced angiogenic effects in human platelets. PAR1 activated platelets released 3 times more VEGF than when activated with PAR4 (Fig. 1A). However, PAR4 activated platelets released 7 times more endostatin than the PAR1 activated platelets (Fig. 1B). Further, PAR1 induced anti-inflammatory effects in human platelets; it did not change IL-1R-A (Fig. 2A) but decreased HMGB-1 levels (Fig. 2B). In contrast, PAR4 stimulated inflammatory effects in human platelets by lowering IL-1-RA and increasing HMGB-1 levels. Conclusion: Our findings indicate that PAR1 induces angiogenetic and anti-inflammatory effects in human platelets, while PAR4 has anti-angiogenetic and inflammatory effects. Of significance is HMGB-1, which is constitutively expressed in the nuclei of most mammalian cells. Under cellular stress, HMGB1 is released into the extracellular matrix and activates the immune response thus acting as a danger-signal. Both PAR1 and PAR4 selectively regulated the release of VEGF and endostatin, and IL-1RA and HMGB-1 from human platelets. Therefore, the role of PAR1 and PAR4 on human platelet activation and inflammation should be considered prior to the use of PRP to treat tendon injuries.

Published
2016

15. Selectively activated PRP exerts differential effects on tendon stem/progenitor cells and tendon healing

Author

Jianying Zhang, Daibang Nie, Kelly Williamson, Jorge L Rocha, MaCalus V Hogan, and James H-C Wang

Subjects
Biochemistry, QD415-436
Abstract

To understand the variable efficacy with platelet rich plasma (PRP) treatments for tendon injury, we determined the differential effects of proteinase-activated receptor (PAR)1- or PAR4-activated PRP (PAR1-PRP, PAR4-PRP) from humans on human patellar tendon stem/progenitor cells (TSCs) and tendon healing. We show that PAR1-PRP released VEGF, whereas PAR4-PRP released endostatin. Treatment of TSCs with PAR1-PRP increased collagen I expression and matrix metalloproteinase-1 (MMP-1), but cells treated with PAR4-PRP increased less collagen I and higher MMP-2 expression. The wound area treated with PAR4-PRP formed tendon-like tissues with well-organized collagen fibers and fewer blood vessels, while PAR1-PRP treatment resulted in the formation of blood vessels and unhealed tissues. These findings indicate that differential activation of PRP leads to different effects on TSCs and tendon healing. We suggest that based on acute or chronic type of tendon injury, selective activation of PRP should be applied in clinics in order to treat injured tendons successfully.

Published
2019
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16. Characterization of the structure, cells, and cellular mechanobiological response of human plantar fascia

Author

Jianying Zhang, Daibang Nie, Jorge L Rocha, MaCalus V Hogan, and James H-C Wang

Subjects
Biochemistry, QD415-436
Abstract

In this study, we report that human plantar fascia consists of two distinct tissues with differential structural properties. These tissues also contain stem/progenitor cells with differential biological properties. The mechanobiological responses of these two plantar fascia stem cells also differ in terms of expression of collagen I and IV, non-ligament-related genes, and proinflammatory genes. The production of inflammatory agents (prostaglandin E 2 , interleukin-6) and matrix degradative enzymes (matrix metalloproteinase-1, matrix metalloproteinase-2) are also different between the two types of plantar fascia stem cells. Based on the findings from this study, we suggest that plantar fasciitis results from the aberrant mechanobiological responses of the stem cells from plantar fascia sheath and core tissues. Our findings may also be used to devise tissue engineering approaches to treat plantar fascia injury effectively.

Published
2018
Full Text
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