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1. Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta‐analysis of the management outcome studies

Author

Jean-Christophe Lega, D. Belzile, Caroline Lambert, S. Provencher, Laurent Bertoletti, Yves Lacasse, and S. Jacquet

Subjects
medicine.medical_specialty, Time Factors, Computed Tomography Angiography, MEDLINE, Pulmonary Artery, 030204 cardiovascular system & hematology, Cochrane Library, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Risk Factors, Internal medicine, Prevalence, medicine, Pulmonary angiography, Humans, cardiovascular diseases, 030212 general & internal medicine, Prospective cohort study, business.industry, Reproducibility of Results, Venous Thromboembolism, Hematology, Prognosis, medicine.disease, Pulmonary embolism, Pre- and post-test probability, Predictive value of tests, Meta-analysis, Pulmonary Embolism, business
Abstract

Essentials Computed tomographic pulmonary angiography (CTPA) is used to exclude pulmonary embolism. This meta-analysis explores the occurrence of venous thromboembolic events (VTE) after a CTPA. Occurrence of VTE after a negative CTPA is ˜8% in study subgroups with a prevalence of PE ≥ 40%. CTPA may be insufficient to safely rule out VTE as a stand-alone diagnostic test for this subgroup. SUMMARY Background Outcome studies have reported the safety of computed tomographic pulmonary angiography (CTPA) as a stand-alone imaging technique to rule out pulmonary embolism (PE). Whether this can be applied to all clinical probabilities remains controversial. Objectives We performed a meta-analysis to determine the proportion of patients with venous thromboembolic events (VTE) despite a negative CTPA according to pretest PE prevalence. Methods We searched MEDLINE, EMBASE and the Cochrane Library (January 1990 to May 2017) for outcome studies recruiting patients with suspected PE using CTPA as a diagnostic strategy. The primary outcome was the cumulative occurrence of VTE at 3 months following a negative CTPA. Results Twenty-two different studies were identified. VTE was confirmed in 2.4% of patients (95% CI, 1.3-3.8%) either at the time of the index event or in the 3 months follow-up. Subgroup analyses suggested that the cumulative occurrence of VTE was related to pretest prevalence of PE, as VTE occurred in 1.8% (95% CI, 0.5-3.7%), 1.4% (95% CI, 0.7-2.3%), 1.0% (95% CI, 0.5-1.8%) and 8.1% (95% CI, 3.5-14.5%) of subgroups of patients with a PE prevalence < 20%, 20-29%, 30-39% and ≥ 40%, respectively. This was further confirmed using meta-regression analysis. Conclusions The negative predictive value of CTPA for VTE varies according to pretest prevalence of PE, and is likely to be insufficient to safely rule out VTE as a stand-alone diagnostic test amongst patients at the highest pretest probability of VTE. Prospective studies are required to validate the appropriate diagnostic algorithm for this subgroup of patients.

Published
2018
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2. Trial Duration and Risk Reduction in Combination Therapy Trials for Pulmonary Arterial Hypertension

Author

Yves Lacasse, Annie-Christine Lajoie, Sébastien Bonnet, Serge Simard, Gabriel Lauzière, Jean-Christophe Lega, Caroline Lambert, S. Provencher, and Charles-Antoine Guay

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Combination therapy, business.industry, Absolute risk reduction, 030204 cardiovascular system & hematology, Cochrane Library, Critical Care and Intensive Care Medicine, Surgery, law.invention, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, health services administration, Internal medicine, Relative risk, Meta-analysis, Number needed to treat, medicine, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business
Abstract

Background Relative risk (RR) and number needed-to-treat (NNT) are frequently time-dependant measures. We performed a systematic review and meta-analysis to assess whether trial duration influenced the relative and absolute risk of worsening in randomized controlled trials (RCTs) comparing combination therapy (CT) of pulmonary arterial hypertension (PAH)-specific therapies vs monotherapy (MT). Methods We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to September 2016) for RCTs assessing CT compared with MT in PAH. The primary outcome was the risk of clinical worsening. We assessed whether trial duration correlated with RR and NNT using weighted meta-regression with mixed effects. Changes in NNT overtime were also assessed using data from long-term event-driven trials. Results There were 3,801 patients throughout 15 studies included. The RR for clinical worsening positively correlated with trial duration ( R 2 = 0.67, P = .0002), whereas the NNT did not (mean NNT, 7; R 2 = 0.02; P = .65). Among long-term event-driven trials, the mean NNT progressively decreased until 52 weeks of follow-up, being stable thereafter. Conversely, the mean RR progressively increased from approximately 0.40 at week 16 to approximately 0.68 at week 104. Conclusions Absolute risk reduction of clinical worsening was relatively constant beyond 6 to 12 months of treatment in clinical trials comparing CT with MT in PAH. These results question the need for CT trials of very long duration in PAH.

Published
2018
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3. Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

Author

Marie-Claude Lampron, Jolyane Meloche, Olivier Boucherat, Eve Tremblay, Steeve Provencher, Roxane Paulin, Caroline Lambert, Mélanie Maltais, Eric Charbonneau, Sandra Breuils-Bonnet, Geraldine Vitry, Sébastien Bonnet, Valérie Nadeau, and François Potus

Subjects
Male, 0301 basic medicine, Pathology, Poly (ADP-Ribose) Polymerase-1, Apoptosis, Cell Cycle Proteins, Coronary Artery Disease, 030204 cardiovascular system & hematology, Muscle, Smooth, Vascular, Epigenesis, Genetic, Rats, Sprague-Dawley, Coronary artery disease, 0302 clinical medicine, RNA, Small Interfering, Cells, Cultured, Nuclear Proteins, Coronary Vessels, Phenotype, medicine.anatomical_structure, Cardiology, RNA Interference, Inflammation Mediators, medicine.symptom, Cardiology and Cardiovascular Medicine, Artery, medicine.medical_specialty, Hypertension, Pulmonary, Myocytes, Smooth Muscle, Inflammation, Vascular Remodeling, Biology, Article, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, Genetic Predisposition to Disease, In patient, Epigenetics, Cell Proliferation, Interleukin-6, Vascular disease, medicine.disease, Comorbidity, Pulmonary hypertension, Disease Models, Animal, MicroRNAs, 030104 developmental biology, Case-Control Studies, DNA Damage, Transcription Factors
Abstract

Objective—Pulmonary arterial hypertension (PAH) is a vascular disease not restricted to the lungs. Many signaling pathways described in PAH are also of importance in other vascular remodeling diseases, such as coronary artery disease (CAD). Intriguingly, CAD is 4× more prevalent in PAH compared with the global population, suggesting a link between these 2 diseases. Both PAH and CAD are associated with sustained inflammation and smooth muscle cell proliferation/apoptosis imbalance and we demonstrated in PAH that this phenotype is, in part, because of the miR-223/DNA damage/Poly[ADP-ribose] polymerase 1/miR-204 axis activation and subsequent bromodomain protein 4 (BRD4) overexpression. Interestingly, BRD4 is also a trigger for calcification and remodeling processes, both of which are important in CAD. Thus, we hypothesize that BRD4 activation in PAH influences the development of CAD.Approach and Results—PAH was associated with significant remodeling of the coronary arteries in both human and experimental models of the disease. As observed in PAH distal pulmonary arteries, coronary arteries of patients with PAH also exhibited increased DNA damage, inflammation, and BRD4 overexpression. In vitro, using human coronary artery smooth muscle cells from PAH, CAD and non-PAH–non-CAD patients, we showed that both PAH and CAD smooth muscle cells exhibited increased proliferation and suppressed apoptosis in a BRD4-dependent manner. In vivo, improvement of PAH by BRD4 inhibitor was associated with a reduction in coronary remodeling and interleukin-6 expression.Conclusions—Overall, this study demonstrates that increased BRD4 expression in coronary arteries of patient with PAH contributes to vascular remodeling and comorbidity development.

Published
2017
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4. Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Author

Rustam Al-Shahi Salman, David P Minks, Dipayan Mitra, Mark A Rodrigues, Priya Bhatnagar, Johann C du Plessis, Yogish Joshi, Martin S Dennis, Gordon D Murray, David E Newby, Peter A G Sandercock, Nikola Sprigg, Jacqueline Stephen, Cathie L M Sudlow, David J Werring, William N Whiteley, Joanna M Wardlaw, Philip M White, Colin Baigent, Daniel Lasserson, Frank Sullivan, Johanna Carrie, Javier Rojas, Shannon Amoils, John Bamford, Jane Armitage, Gabriel Rinkel, Gordon Lowe, Jonathan Emberson, Karen Innes, Lynn Dinsmore, Jonathan Drever, Carol Williams, David Perry, Connor McGill, David Buchanan, Allan Walker, Aidan Hutchison, Christopher Matthews, Ruth Fraser, Aileen McGrath, Ann Deary, Rosemary Anderson, Pauli Walker, Christian Hansen, Richard Parker, Aryelly Rodriguez, Malcolm Macleod, Thomas Gattringer, Jeb Palmer, Eleni Sakka, Jennifer Adil-Smith, David Minks, Johannes du Plessis, Christine Lerpiniere, Richard O'Brien, Seona Burgess, Gillian Mead, Ruth Paulton, Fergus Doubal, Katrina McCormick, Neil Hunter, Pat Taylor, Ruwan Parakramawansha, Jack Perry, Gordon Blair, Allan MacRaild, Adrian Parry-Jones, Mary Johnes, Stephanie Lee, Kelly Marie Shaw, Ilse Burger, Martin Punter, Andrea Ingham, Jane Perez, Zin Naing, Jordi Morell, Tracy Marsden, Andrea Hall, Sally Marshall, Louise Harrison, Rowilson Jarapa, Edith Wood, Victoria O'Loughlin, David Cohen, Silvie Davies, Kelechi Njoku, Mushiya Mpelembue, Laura Burgess, Radim Licenik, Mmua Ngwako, Nabeela Nisar, Rangah Niranchanan, Tatjana Roganova, Rajaram Bathula, Joseph Devine, Anette David, Anne Oshodi, Fenglin Guo, Emmanuelle Owoyele, Varthi Sukdeo, Robert Ballantine, Mudhar Abbdul-saheb, Angela Chamberlain, Aberami Chandrakumar, Philip Poku, Kirsty Harkness, Catrin Blank, Emma Richards, Ali Ali, Faith Kibutu, Olesia Balitska, Kathryn Birchall, Pauline Bayliss, Clare Doyle, Kathy Stocks, Arshad Majis, Jo Howe, Christine Kamara, Luke Barron, Ahmad Maatouk, Ralf Lindert, Katy Dakin, Jessica Redgrave, Biju Bhaskaran, Isam Salih, Debs Kelly, Susan Szabo, Dawn Tomlin, Helen Bearne, Jean Buxton, Pauline Fitzell, Georgina Ayres, Afaq Saulat, Kathleen Horan, Joanne Garfield-Smith, Harbens Bhakri, Paul Guyler, Devesh Sinha, Thayalini Loganathan, Amber Siddiqui, Anwer Siddiqui, Lucy Coward, Swapna Kunhunny, Sharon Tysoe, Rajalakshmi Orath Prabakaran, Shyam Kelavkar, Sindhu Rashmi, David Ngo, Kheng Xiong Ng, Nisha Menon, Sweni Shah, Mark Barber, Derek Esson, Fiona Brodie, Talat Anjum, Mushtaq Wani, Manju Krishnan, Leanne Quinn, Jayne Spencer, Terry Jones, Helen Thompson-Jones, Lynne Dacey, Srikanth Chenna, Sharon Storton, Sarah Thomas, Teresa Beaty, Shelley Treadwell, Caroline Davies, Susan Tucker, Lynda Connor, Peter Slade, Glyn Gainard, Girish Muddegowda, Ranjan Sanyal, Alda Remegoso, Nenette Abano, Chelsea Causley, Racquel Carpio, Stephanie Stevens, Adrian Butler, Resti Varquez, Hayley Denic, Francis Alipio, Andrew Moores, Adrian Barry, Holly Maguire, Jeanette Grocott, Kay Finney, Sue Lyjko, Christine Roffe, Joanne Hiden, Phillip Ferdinand, Vera Cvoro, Khalil Ullah, Nicola Chapman, Mandy Couser, Susan Pound, Sean Mcauley, Senthil Raghunathan, Faye Shelton, Amanda Hedstrom, Margi Godfrey, Diane Havard, Amanda Buck, Kailash Krishnan, Nicola Gilzeane, Jack Roffe, Judith Clarke, Katherine Whittamore, Saima Sheikh, Rekha Keshvara, Carla Jordan, Benjamin Jackson, Gwendoline Wilkes, Jason Appleton, Zhe Law, Oliver Matias, Evangelos Vasileiadis, Cathy Mason, Anthea Parry, Geraldine Landers, Melinda Holden, Basaam Aweid, Khalid Rashed, Linda Balian, Carinna Vickers, Elizabeth Keeling, Sarah Board, Joanna Allison, Clare Buckley, Barbara Williams-Yesson, Joanne Board, Tressy Pitt-Kerby, Alfonso Tanate, Diane Wood, Manohar Kini, Dinesh Chadha, Deborah Walstow, Rosanna Fong, Robert Luder, Tolu Adesina, Jill Gallagher, Hayley Bridger, Elodie Murali, Maneesh Bhargava, Chloe van Someren, Frances Harrington, Abhijit Mate, Ali James, Gillian Courtauld, Christine Schofield, Katja Adie, Linda Lucas, Kirsty Bond, Bev Maund, Sam Ellis, Paul Mudd, Martin James, Samantha Keenan, Angela Bowring, Julie Cageao, Hayley Kingwell, Caroline Roughan, Anthony Hemsley, Jane Sword, David Strain, Keniesha Miller, Anita Goff, Karin Gupwell, Kevin Thorpe, Hedley Emsley, Shuja Punekar, Alison McLoughlin, Sulaiman Sultan, Bindu Gregory, Sonia Raj, Donna Doyle, Keith Muir, Wilma Smith, Angela Welch, Fiona Moreton, Bharath Kumar Cheripelli, Salwa El Tawil, Dheeraj Kalladka, Xuya Huang, Nicola Day, Sankaranarayanan Ramachandran, Caroline Crosbie, Jennifer Elliot, Tony Rudd, Katherine Marks, Ajay Bhalla, Jonathan Birns, Sagal Kullane, Nic Weir, Christopher Allen, Vanessa Pressly, Pam Crawford, Emma Battersby-Wood, Alex Blades, Shuna Egerton, Ashleigh Walters, Sue Evans, James Richard Marigold, Fiona Smith, Gabriella Howard, Imogen Gartrell, Simon Smith, Robyn Creeden, Chloe Cox, Cherish Boxall, Jonathan Hewitt, Claire Nott, Procter Sarah, Jessica Whiteman, Steve Buckle, Rebecca Wallace, Rina Mardania, Jane Gray, Claire Triscott, Anand Nair, Jill Greig, Pratap Rana, Matthew Robinson, Mohammad Irfan Alam, David Werring, Duncan Wilson, Caroline Watchurst, Maria Brezitski, Luci Crook, Ifan Jones, Azra Banaras, Krishna Patel, Renuka Erande, Caroline Hogan, Isabel Hostettler, Amy Ashton, Shez Feerick, Nina Francia, Nnebuife Oji, Emma Elliott, Talal Al-Mayhani, Martin Dennis, Cathie Sudlow, William Whiteley, Dipankar Dutta, Pauline Brown, Deborah Ward, Fiona Davis, Jennifer Turfrey, Chloe Hughes, Kayleigh Collins, Rehana Bakawala, Susan O'Connell, Jon Glass, David Broughton, Dinesh Tryambake, Lynn Dixon, Kath Chapman, Andrew Young, Adrian Bergin, Andrew Sigsworth, Aravind Manoj, Glyn Fletcher, Paula Lopez, Penelope Cox, Mark Wilkinson, Paul Fitzsimmons, Nikhil Sharma, James Choulerton, Denise Button, Lindsey Dow, Lukuman Gbadamoshi, Joanne Avis, Barbara Madigan, Stephanie McCann, Louise Shaw, Deborah Howcroft, Suzanne Lucas, Andrew Stone, Gillian Cluckie, Caroline Lovelock, Brian Clarke, Neha Chopra, Natasha Clarke, Bhavini Patel, Kate Kennedy, Rebecca Williams, Adrian Blight, Joanna O'Reilly, Chukwuka Orefo, Nilofer Dayal, Rita Ghatala, Temi Adedoyin, Fran Watson, Sarah Trippier, Lillian Choy, Barry Moynihan, Usman Khan, Val Jones, Naomi Jeyaraj, Lourda Kerin, Kamy Thavanesan, Divya Tiwari, Chantel Cox, Anja Ljubez, Laura Tucker, Arshi Iqbal, Caroline Bagnall, Marketa Keltos, Josh Roberts, Becky Jupp, Catherine Ovington, Emily Rogers, Owen David, Jo Bell, Barbara Longland, Gail Hann, Martin Cooper, Mohammad Nasar, Anoja Rajapakse, Inez Wynter, Ijaz Anwar, Helen Skinner, Tarn Nozedar, Damian McArdle, Balakrishna Kumar, Susan Crawford, Arunkumar Annamalai, Alex Ramshaw, Clare Holmes, Sarah Caine, Mairead Osborn, Emily Dodd, Peter Murphy, Nicola Devitt, Pauline Baker, Amy Steele, Lucy Belle Guthrie, Samantha Clarke, Ahamad Hassan, Dean Waugh, Emelda Veraque, Linetty Makawa, Mary Kambafwile, Marc Randall, Vasileios Papavasileiou, Claire Cullen, Jenny Peters, Hlaing Thant, Tanya Ingram, Mellor Zoe, Ramesh Durairaj, Melanie Harrison, Sarah Stevenson, Daniela Shackcloth, Jordan Ewing, Victoria Sutton, Mark McCarron, Jacqueline McKee, Mandy Doherty, Ferghal McVerry, Caroline Blair, Mary MacLeod, Janice Irvine, Heather Gow, Jacqueline Furnace, Anu Joyson, Baljit Jagpal, Sarah Ross, Katrina Klaasen, Sandra Nelson, Rebecca Clarke, Nichola Crouch, Beverly MacLennan, Vicky Taylor, Daniel Epstein, Avani Shukla, Vinodh Krishnamurthy, Paul Nicholas, Sammie Qureshi, Adam Webber, Justin Penge, Hawraman Ramadan, Stuart Maguire, Chris Patterson, Ruth Bellfield, Brigid Hairsine, Kelvin Stewart, Michaela Hooley, Outi Quinn, Bella Richard, Sally Moseley, Mandy Edwards, Heidi Lawson, Michelle Tayler, Yogish Pai, Mahesh Dhakal, Bernard Esisi, Sofia Dima, Gemma Marie Smith, Mark Garside, Muhammad Naeem, Vidya Baliga, Gill Rogers, Ellen Brown, David Bruce, Rachel Hayman, Susan Clayton, Ed Gamble, Rebecca Grue, Bethan Charles, Adam Hague, Sujata Blane, Caroline Lambert, Afnan Chaudhry, Thomas Harrison, Kari Saastamoinen, Dionne Hove, Laura Howaniec, Gemma Grimwood, Ozlem Redjep, Fiona Humphries, Lucia Argandona, Larissa Cuenoud, Esther Erumere, Sageet Amlani, Grace Auld, Afraim Salek-Haddadi, Ursula Schulz, James Kennedy, Gary Ford, Philip Mathieson, Ian Reckless, Rachel Teal, Giulia Lenti, George Harston, Eoin O'Brien, Joanne Mcgee, Jennifer Mitchell, Elaine Amis, Dominic Handley, Siobhan Kelly, George Zachariah, Jobbin Francis, Sarah Crisp, Juliana Sesay, Sarah Finlay, Helen Hayhoe, Niamh Hannon, Tom Hughes, Bethan Morse, Henry De Berker, Emma Tallantyre, Ahmed Osman, Susan White, Stefan Schwarz, Benjamin Jelley, Rajendra Yadava, Khalid Azhar, Julie Reddan, Mirriam Sangombe, Samantha Stafford, Ken Fotherby, Debbie Morgan, Farrukh Baig, Karla Jennings-Preece, Donna Butler, Nasar Ahmad, Angela Willberry, Angela Stevens, Baljinder Rai, Prasad Siddegowda, Peter Howard, Lisa Hyatt, Tracey Dobson, David Jarrett, Suheil Ponnambath, Jane Tandy, Yasmin Harrington-Davies, Rebecca Butler, Claire James, Stacey Valentine, Anne Suttling, Peter Langhorne, Gillian Kerr, Fiona Wright, Ruth Graham, Christine McAlpine, Mohammad Shahzad Iqbal, Louise Humphreys, Kath Pasco, Olga Balazikova, Ashraf Nasim, Cassilda Peixoto, Louise Gallagher, Shahrzad Shahmehri, Sandip Ghosh, Elizabeth Barrie, Danielle Gilmour, Margo Henry, Tom Webb, Linda Cowie, Hannah Rudenko, Shanni McDonald, Natasha Schumacher, Susannah Walker, Tracey Cosier, Anna Verrion, Eva Beranova, Audrey Thomson, Marius Venter, Arindam Kar, Sheila Mashate, Kirsten Harvey, Léjeune Gardener, Vinh Nguyen, Omid Halse, Olivia Geraghty, Beth Hazel, Peter Wilding, Victoria Tilley, Tim Cassidy, Beverley McClelland, Maria Bokhari, Timothy England, Mohana Maddula, Richard Donnelly, Paul Findlay, Ashish Macaden, Ian Shread, Charlotte Barr, Azlisham Mohd Nor, Claire Brown, Nicola Persad, Charlotte Eglinton, Marie Weinling, Benjamin Hyams, Alex Shah, John Baker, Anthony Byrne, Caroline McGhee, Amanda Smart, Claire Copeland, Michael Carpenter, Marion Walker, Richard Davey, Ann Needle, Razik Fathima, Gavin Bateman, Prabal Datta, Andrew Stanners, Linda Jackson, Julie Ball, Michelle Davis, Natalie Atkinson, Michelle Fawcett, Teresa Thompson, Helen Guy, Valerie Hogg, Carole Hays, Stephen Woodward, Mohammad Haque, Eluzai Hakim, Stuart Symonds, Mehran Maanoosi, Jane Herman, Toby Black, Skelton Miriam, Caroline Clarke, Alpha Anthony, Michele Tribbeck, Julie Cronin, Denise Mead, Ruth Fennelly, James McIlmoyle, Christina Dickinson, Carol Jeffs, Sajjad Anwar, Joanne Howard, Kirsty Jones, Saikat Dhar, Caroline Clay, Muhammad Siddiq, Simone Ivatts, Yolanda Baird, Moore Sally, Isobel Amey, Sophie Newton, Lisa Clayton-Evans, Indra Chadbourn, Rayessa Rayessa, Charde Naylor, Alicia Rodgers, Lisa Wilson, Sarah Wilson, Emma Clarkson, Ruth Davies, Paula Owings, Graeme Sangster, Valerie Gott, Victoria Little, Pauline Weir, Suja Cherian, Deepa Jose, Helen Moroney, Susan Downham, Angela Dodd, Venetia Vettimootal Johnson, Laura Codd, Naomi Robinson, Ashraf Ahmed, Mo Albazzaz, Sharon Johnson, Carol Denniss, Mishell Cunningham, Tajammal Zahoor, Timothy Webster, Sandra Leason, Syed Haider, Kausic Chatterjee, Arumugam Nallasivan, Charlotte Perkins, Samantha Seagrave, Colin Jenkins, Fiona Price, Claire Hughes, Lily Mercer, Malik Hussain, Sarah Brown, Miriam Harvey, Jane Homan, Mohammad Khan, Robert Whiting, Leanne Foote, Nicholas Hunt, Helen Durman, Lucy Brotherton, Jayne Foot, Corinne Pawley, Eliza Foster, Alison Whitcher, Kneale Metcalf, Jenny Jagger, Susan McDonald, Kelly Waterfield, Patrick Sutton, Naval Shinh, Ajmal Anversha, Garth Ravenhill, Richard Greenwood, Janak Saada, Alison Wiltshire, Rebekah Perfitt, Sreeman Andole, Naveen Gadapa, Karen Dunne, Magdalini Krommyda, Evelyne Burssens, Sam King, Catherine Plewa, Nigel Smyth, Jenny Wilson, Elio Giallombardo, Lucy Sykes, Pradeep Kumar, James Barker, Isabel Huggett, Linda Dunn, Charlotte Culmsee, Philip Thomas, Min Myint, Helen Brew, Nikhil Majmudar, Janice OConnell, George Bunea, Charlotte Fox, Diane Gulliver, Andrew Smith, Betty Mokoena, Naweed Sattar, Ramesh Krishnamurthy, Emily Osborne, David Wilson, Belinda Wroath, Kevin Dynan, Michael Power, Susan Thompson, Victoria Adell, Enoch Orugun, Una Poultney, Rachel Glover, Hannah Crowther, Sarah Thornthwaite, Ivan Wiggam, Aine Wallace, Enda Kerr, Ailsa Fulton, Annemarie Hunter, Suzanne Tauro, Sarah Cuddy, David Mangion, Anne Hardwick, Skarlet Markova, Tara Lawrence, Carmen Constantin, Jo Fletcher, Isobel Thomas, Kerry Pettitt, Lakshmanan Sekaran, Margaret Tate, Kiranjit Bharaj, Rohan Simon, Frances Justin, Sakthivel Sethuraman, Duke Phiri, Niaz Mohammed, Meena Chauhan, Khaled Elfandi, Uzma Khan, David Eveson, Amit Mistri, Lisa Manning, Shagufta Khan, Champa Patel, Mohammed Moqsith, Saira Sattar, Man Yee Lam, Kashif Musarrat, Claire Stephens, Latheef Kalathil, Richard Miller, Maqsud Salehin, Nikki Gautam, Duncan Bailey, Kelly Amor, Julie Meir, Anne Nicolson, Javed Imam, Lisa Wood, Julie White, Mahmud Sajid, George Ghaly, Margaret Ball, Rachel Gascoyne, Harald Proeschel, Simon Sharpe, Sarah Horton, Emily Beaves, Stephanie Jones, Brigitte Yip, Murdina Bell, Linda MacLiver, Brian MacInnes, Don Sims, Jennifer Hurley, Mark Willmot, Claire Sutton, Edward Littleton, Susan Maiden, Rachael Jones, James Cunningham, Carole Green, Michelle Bates, Raj Shekhar, Ellie Gilham, Iman Ahmed, Rachel Crown, Tracy Fuller, Neetish Goorah, Angela Bell, Christine Kelly, Arun Singh, Jamie Walford, Benjamin Tomlinson, Farzana Patel, Stephen Duberley, Ingrid Kane, Chakravarthi Rajkumar, Jane Gaylard, Joanna Breeds, Nicola Gainsborough, Alexandra Pitt-Ford, Emma Barbon, Laura Latter, Philip Thompson, Simon Hervey, Shrivakumar Krishnamoorthy, Joseph Vassallo, Deborah Walter, Helen Cochrane, Meena Srinivasan, Robert Campbell, Denise Donaldson, Nichola Motherwell, Frances Hurford, Indranil Mukherjee, Antony Kenton, Sheila Nyabadza, Irene Martin, Benjamin Hunt, Hardi Hassan, Sarah O'Toole, Bander Dallol, Janet Putterill, Ratneshwari Jha, Rachel Gallifent, Puneet Kakar, Aparna Pusalkar, kelly Chan, Puneet Dangri, Hannah Beadle, Angela Cook, Karen Crabtree, Santhosh Subramonian, Peter Owusu-Agyei, Natalie Temple, Nicola Butterworth-Cowin, Suzanne Ragab, Kerstin Knops, Emma Jinks, Christine Dickson, Laura Gleave, Judith Dube, Jacqui Leggett, Tatiana Garcia, Sissy Ispoglou, Rachel Evans, Sandeep Ankolekar, Anne Hayes, Hlaing Ni, Bithi Rahman, Josette Milligan, Carol Graham, Josin Jose, Breffni Keegan, Jim Kelly, Richard Dewar, James White, Kelly Thomas, Rajkumar, C, University of St Andrews. School of Medicine, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Population and Behavioural Science Division, University of St Andrews. Pure Mathematics, University of St Andrews. School of Psychology and Neuroscience, and University of St Andrews. School of Biology

Subjects
Male, MICROBLEEDS, 030204 cardiovascular system & hematology, AMYLOID ANGIOPATHY, Brain Ischemia, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Secondary Prevention, ACUTE ISCHEMIC-STROKE, Aged, 80 and over, Aspirin, Manchester Cancer Research Centre, medicine.diagnostic_test, Hazard ratio, Brain, Magnetic Resonance Imaging, Superficial siderosis, Cerebral Small Vessel Diseases, Stroke, Treatment Outcome, Female, medicine.drug, CT, medicine.medical_specialty, ANTITHROMBOTIC THERAPY, Clinical Neurology, Neuroimaging, Subgroup analysis, 03 medical and health sciences, Internal medicine, medicine, Journal Article, Humans, Aged, Cerebral Hemorrhage, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, DAS, Magnetic resonance imaging, medicine.disease, SIGNS, ASPIRIN, Neurology (clinical), Tomography, X-Ray Computed, business, SUPERFICIAL SIDEROSIS, Platelet Aggregation Inhibitors, 030217 neurology & neurosurgery
Abstract

Background: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy.Methods: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627.Findings: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05).Interpretation: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision.Funding: British Heart Foundation.

Published
2019
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5. The psychosocial complexities of acute burn patients in an Australian trauma hospital

Author

Louise Harms, Eldho Paul, Rose Knol, Emma Kelly, Anna Wellington-Boyd, Caroline Lambert, and Heather Cleland

Subjects
Male, Body Surface Area, Burn Units, Psychological intervention, Comorbidity, Critical Care and Intensive Care Medicine, Social Networking, 030207 dermatology & venereal diseases, 0302 clinical medicine, Residence Characteristics, Risk Factors, Economic Status, Mental Competency, Young adult, Aged, 80 and over, Geography, Medical record, Mental Disorders, Age Factors, General Medicine, Emigration and Immigration, Middle Aged, Patient Discharge, Distress, Emergency Medicine, Female, Burns, Psychosocial, Adult, Employment, medicine.medical_specialty, Adolescent, Substance-Related Disorders, Vulnerable Populations, 03 medical and health sciences, Patient safety, Young Adult, medicine, Humans, Family, Aged, Retrospective Studies, Jurisprudence, business.industry, Australia, Psychosocial Support Systems, Social Support, 030208 emergency & critical care medicine, Retrospective cohort study, Length of Stay, Protective Factors, medicine.disease, Brain Injuries, Emergency medicine, Housing, Surgery, Nervous System Diseases, business
Abstract

Psychosocial risk and protective factors specific to acute burn patients have been shown to impact on longer-term health outcomes. Yet the nature and impact of such factors throughout the acute hospital admission phase have not been extensively examined to date. This study analysed the psychosocial pre-admission, hospitalisation and discharge factors for a sample of burn patients at an Australian specialist acute burns unit (The Alfred) and the relationship with their admission length.A retrospective audit was undertaken of psychosocial factors documented in patient medical records, Victorian Adult Burns Service registry data, and social work files (January-December 2014).Two hundred and forty-nine patients were identified, with a mean age of 42.83 years and a preponderance of men (73.9%). The majority (71%) had a low burn severity (10%), and an average of eight psychosocial factors. Independent of the severity of the burn, two psychosocial domains were strongly predictive of length of stay - coping with treatment and discharge planning - along with pre-existing psychosocial factors and family support.A diversity of psychosocial factors was identified, highlighting the clinical complexity of this patient group. Given three domains of admission-related psychosocial factors were predictive of the length of patient stay, more targeted psychosocial interventions in these areas may ensure patients and their families are supported more effectively throughout an admission, and length of stay costs may also be reduced.

Published
2019

6. Abstract WP367: Effect of the Introduction of a New Pathway for Prevention of Venous Thromboembolisim (VTE) Including Neuromuscular Electrical Stimulation (NMES) on Symptomatic VTE on Immobile Stroke Patients

Author

Lucy Richards, Christine Roffe, Jodie Williams, Indira Natarajan, Caroline Lambert, and Claire Moss

Subjects
Advanced and Specialized Nursing, medicine.medical_specialty, Stroke patient, business.industry, Intermittent pneumatic compression, Stimulation, 030204 cardiovascular system & hematology, medicine.disease, 03 medical and health sciences, Venous thrombosis, 0302 clinical medicine, Internal medicine, medicine, Cardiology, cardiovascular diseases, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Stroke, Venous thromboembolism, 030217 neurology & neurosurgery
Abstract

Background: Venous Thromboembolism (VTE) prophylaxis using Intermittent Pneumatic Compression (IPC) is not possible in all stroke patients. We introduced a new VTE pathway which includes Neuromuscular Electrical Stimulation of the peroneal nerve using the geko TM device (Firstkind Ltd UK) as an alternative prevention strategy for this patient group. In addition, compliance with VTE prophylaxis was reviewed 4-hourly as part of comfort rounds. Methods: This is a prospective audit of the new pathway. All stroke patients admitted to the Acute Stroke Unit at Royal Stoke University Hospital between 1 Nov 2016 and 3 Mar 2018 were included. In line with UK guidelines patients unable to mobilize independently were prescribed IPC in addition to standard measures, e.g. hydration, mobilization, and aspirin where indicated, unless patients were palliative, fully anticoagulated, or refused the intervention. Patients who could not use IPC (intolerance, falls risk, out of stock) were switched to the geko TM device. Results: In total 999 stroke patients were included. Of these 187 (18.7%) required no prophylaxis, 125 (12.5%) were fully anti-coagulated, and 687 (68.7%) required mechanical VTE prophylaxis (MP). Of these 463 (67.3%) received IPC and 122 (17.7%) the geko TM device as their only intervention. A further 81 (11.8%) patients became intolerant to IPC and were prescribed the geko TM as a secondary intervention and 21 (3.1%) refused treatment. The geko TM was used in 203 (29.5% of MP). At 90 days there were 15 (1.5%) VTE (symptomatic DVT or PE). Of these 13 occurred in the MP group: 11 (6 DVT, 5 PE) in the ‘IPC only cohort’, 1 in ‘IPC with secondary geko TM ’, 0 in the ‘geko TM only’ cohort, and 1 (PE) in ‘refused prophylaxis’. A further 2 VTE where recorded: 1 (DVT) in ‘prophylaxis not required’ and 1 (DVT) in ‘on anticoagulant’. The geko TM was used for a mean of 9 days/patient and was well tolerated without serious adverse events. Conclusion: The new strategy of increased surveillance, and use of the geko TM device where indicated, for patients who cannot use IPC was associated with a low overall incidence of symptomatic VTE (1.5%). The incidence in high risk immobile patients requiring MP was 1.9% (13/687), which is lower than the 6.6% in a comparable patient population in the CLOTS-3 study.

Published
2019
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7. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS) : a pragmatic, double-blind, randomised, controlled trial

Author

Martin Dennis, Gillian Mead, John Forbes, Catriona Graham, Maree Hackett, Graeme J Hankey, Allan House, Stephanie Lewis, Erik Lundström, Peter Sandercock, Karen Innes, Carol Williams, Jonathan Drever, Aileen Mcgrath, Ann Deary, Ruth Fraser, Rosemary Anderson, Pauli Walker, David Perry, Connor Mcgill, David Buchanan, Yvonne Chun, Lynn Dinsmore, Emma Maschauer, Amanda Barugh, Shadia Mikhail, Gordon Blair, Ingrid Hoeritzauer, Maggie Scott, Greig Fraser, Katherine Lawrence, Alison Shaw, Judith Williamson, David Burgess, Malcolm Macleod, Dan Morales, Frank Sullivan, Marian Brady, Ray French, Frederike Van Wijck, Caroline Watkins, Fiona Proudfoot, Joanna Skwarski, Diane Mcgowan, Rachael Murphy, Seona Burgess, William Rutherford, Katrina Mccormick, Ruaridh Buchan, Allan Macraild, Ruth Paulton, Adnan Fazal, Pat Taylor, Ruwan Parakramawansha, Neil Hunter, Jack Perry, John Bamford, Dean Waugh, Emelda Veraque, Caroline Bedford, Mary Kambafwile, Luis Idrovo, Linetty Makawa, Paula Smalley, Marc Randall, Tharani Thirugnana-Chandran, Ahamad Hassan, Richard Vowden, Joanne Jackson, Ajay Bhalla, Anthony Rudd, Chi Kai Tam, Jonathan Birns, Charlotte Gibbs, Leonie Lee Carbon, Elizabeth Cattermole, Katherine Marks, Angela Cape, Lisa Hurley, Sagal Kullane, Nigel Smyth, Charlotte Eglinton, Jennifer Wilson, Elio Giallombardo, Angela Frith, Paul Reidy, Matthew Pitt, Lucy Sykes, Deborah Dellafera, Victoria Croome, Lauriane Kerwood, Mirea Hancevic, Christina Narh, Carley Merritt, John Duffy, Duncan Cooke, Juliet Willson, Ali Ali, Aaizza Naqvi, Christine Kamara, Helen Bowler, Simon Bell, Tracy Jackson, Kirsty Harkness, Kathy Stocks, Suzanna Duty, Clare Doyle, Geoffrey Dunn, Keith Endean, Fiona Claydon, Emma Richards, Jo Howe, Ralf Lindert, Arshad Majid, Katy Dakin, Ahmad Maatouk, Luke Barron, Madana Meegada, Pratap Rana, Anand Nair, Christine Brighouse-Johnson, Jill Greig, Myint Kyu, Sanjeev Prasad, Matthew Robinson, Irfan Alam, Belinda Mclean, Lindsay Greenhalgh, Zenab Ahmed, Christine Roffe, Susan Brammer, Carole Beardmore, Kay Finney, Adrian Barry, Paul Hollinshead, Jeanette Grocott, Holly Maguire, Indira Natarajan, Jayan Chembala, Ranjan Sanyal, Sue Lijko, Nenette Abano, Alda Remegoso, Phillip Ferdinand, Stephanie Stevens, Resti Varquez, Chelsea Causley, Adrian Butler, Philip Whitmore, Caroline Stephen, Racquel Carpio, Joanne Hiden, Girish Muddegowda, Hayley Denic, Jane Sword, Ross Curwen, Martin James, Paul Mudd, Fiona Hall, Julie Cageao, Samantha Keenan, Caroline Roughan, Hayley Kingwell, Anthony Hemsley, Christoph Lohan, Sue Davenport, Angela Bowring, Tamika Chapter, Max Hough, David Strain, Karin Gupwell, Keniesha Miller, Anita Goff, Ellie Cusack, Shirley Todd, Rebecca Partridge, Georgiana Jennings, Kevin Thorpe, Jacquelyn Stephenson, Kelly Littlewood, Mark Barber, Fiona Brodie, Steven Marshall, Derek Esson, Irene Coburn, Caroline Mcinnes, Fiona Ross, Emma Bowie, Heather Barcroft, Victoria Withers, Laura Miller, Paul Willcoxson, Michelle Donninson, Richard Evans, Di Daniel, John Coyle, Michael Keeling, Peter Wanklyn, Mark Elliott, John Wightman, Elizabeth Iveson, Natasha Dyer, Anne-Marie Porteous, Monica Haritakis, Mandy Ward, Lucy Doughty, Lisa Carr, Mark O Neill, Cosmas Anazodo, Paul Wood, Poppy Cottrell, Cheryl Donne, Romina Rodriguez, Ruhail Mir, Jax Westmoreland, Judith Bell, Christopher Emms, Lorraine Wright, Pearl Clark Brown, Elizabeth Bamford, Andrew Stanners, Mike Carpenter, Prabal Datta, Richard Davey, Ann Needle, Marjorie Jane Eastwood, Fathima Zeena Razik, Imran Ghouri, Gavin Bateman, Judy Archer, Venkatesh Balasubramanian, Richard Bowers, Julie Ball, Louise Benton, Linda Jackson, Julie Ellam, Kate Norton, Paul Guyler, Terry Dowling, Sharon Tysoe, Paula Harman, Ashish Kundu, Ololade Omodunbi, Thayalini Loganathan, Stuart Chandler, Shanas Noor, Anwer Siddiqui, Amber Siddiqui, Swapna Kunhunny, Devesh Sinha, Martin Sheppard, Sindhu Rashmi, Elena France, Rajalakshmi Orath Prabakaran, Laura Wilson, Amiirah Ropun, Shyam Kelavkar, Kheng Xiong Ng, Lucy Kamuriwo, Sweni Shah, David Mangion, Camen Constantin, Luigi De Michele Hock, Anne Hardwick, Jayne Borley, Skarlet Markova, Kimberley Netherton, Tara Lawrence, Jo Fletcher, Rebecca Spencer, Helen Palmer, Claire Cullen, Dolores Hamill, Ramesh Durairaj, Zoe Mellor, Tanya Fluskey, Diane Wood, Alison Keeling, Victoria Hankin, Jennifer Peters, Daniela Shackcloth, Thant Hlaing, Rebecca Tangney, Jordan Ewing, Melanie Harrison, Sarah Stevenson, Victoria Sutton, Mohamed Soliman, Julia Hindle, Elizabeth Watson, Claire Hewitt, Susie Butler, Ibrahim Wahishi, Sarwat Arif, Amy Fields, Jagdish Sharma, Rose Brown, Caroline Taylor, Sarah Bell, Simon Leach, Chris Patterson, Sophia Khan, Helen Wilson, Joanne Price, Hawraman Ramadan, Stuart Maguire, Ruth Bellfield, Michaela Hooley, Umair Hamid, Waqar Gaba, Robina Ghulam, Leslie Masters, Outi Quinn, Lakshmanan Sekaran, Margaret Tate, Niaz Mohammed, Kiranjit Bharaj, Frances Justin, Rajan Pattni, Lanka Alwis, Sakthivel Sethuraman, Rianne Robinson, Lianne Eldridge, Susan Mintias, Meena Chauhan, Chi-Kai Tam, Jeremias Palmones, Clare Holmes, Lucy Belle Guthrie, Mairead Osborn, Lindsay Ball, Sarah Caine, Amy Steele, Peter Murphy, Nikki Devitt, Jayne Leonard, Ronak Patel, Ian Penwarden, Emily Dodd, Amy Holloway, Pauline Baker, Samantha Clarke, Sandra Williams, Lindsey Dow, Roland Wynn-Williams, James Kennedy, Rachel Teal, Ursula Schulz, Gary Ford, Philip Mathieson, Ian Reckless, Ana Deveciana, Paige Mccann, Gillian Cluckie, Geoffrey Howell, Jonathan Ayer, Barry Moynihan, Rita Ghatala, Brian Clarke, Geoffrey Cloud, Bhavini Patel, Usman Khan, Nia Al-Samarrai, Sarah Trippier, Neha Chopra, Temi Adedoyin, Fran Watson, Val Jones, Liqun Zhang, Lillian Choy, Rebecca Williams, Natasha Clarke, Adrian Blight, Kate Kennedy, Alice Dainty, Johann Selvarajah, Dheeraj Kalladka, Bharath Cheripelli, Wilma Smith, Fiona Moreton, Angela Welch, Xuya Huang, Elizabeth Douglas, Audrey Lush, Nicola Day, Salwa El Tawil, Karen Montgomery, Helen Hamilton, Doreen Ritchie, Sankaranarayanan Ramachandra, Kirsty Mcleish, Kamy Thavanesan, Sathyabama Loganathan, Josh Roberts, Chantel Cox, Sarah Orr, Alison Hogan, Divya Tiwari, Gail Hann, Barbara Longland, Owen David, Jo Bell, Catherine Ovington, Emily Rogers, Rachel Bower, Marketa Keltos, David Cohen, Joseph Devine, Lankantha Alwis, Lucy Southworth, Laura Burgess, Matilda Lang, Bhavna Badiani, Fenglin Guo, Anne Oshodi, Emmanuelle Owoyele, Norah Epie, Anette David, Mushiya Mpelembue, Rajaram Bathula, Mudhar Abdul-Saheb, Angela Chamberlain, Varthi Sudkeo, Khalid Rashed, Barbara Williams-Yesson, Joanne Board, Sarah De Bruijn, Clare Buckley, Sarah Board, Joanna Allison, Elizabeth Keeling, Tracey Duckett, Dave Donaldson, Carinna Vickers, Claire Barron, Linda Balian, Jodhi Wilson, Adam Edwards, Timothy England, Amanda Hedstrom, Elizabeth Bedford, Margaret Harper, Elina Melikyan, Wendy Abbott, Kashmira Subramanian, Marie Goldsworthy, Meena Srinivasan, Angela Yeomans, Denise Donaldson, Frances Hurford, Riquella Chapman, Sana Shahzad, Nicki Motherwell, Louise Tonks, Rachel Young, Usman Ghani, Indranil Mukherjee, Dipankar Dutta, Mudhar Obaid, Pauline Brown, Fiona Davis, Deborah Ward, Jennifer Turfrey, Bethan Cartwright, Bilal Topia, Judith Spurway, Kayleigh Collins, Rehana Bakawala, Chloe Hughes, Susan Oconnell, Linda Hill, Kausik Chatterjee, Tim Webster, Syed Haider, Pamela Rushworth, Fiona Macleod, Arumugam Nallasivan, Charlotte Perkins, Edel Burns, Sandra Leason, Tom Carter, Samantha Seagrave, Eman Sami, Lisa Armstrong, Syed Naseem Naqvi, Muhammad Hassan, Sharron Parkinson, Samantha Mawer, Gillian Darnbrook, Carl Booth, Brigid Hairsine, Matthew Smith, Sue Williamson, Fiona Farquhar, Bernard Esisi, Tim Cassidy, Gavin Mankin, Beverley Mcclelland, Maria Bokhari, David Sproates, Elliot Epstein, Steve Hurdowar, Ruth Blackburn, Nazran Sukhdeep, Saika Razak, Khalid Osman, Amina Hashmi, Natasha Upton, Frances Harrington, Gillian Courtauld, Christine Schofield, Linda Lucas, Katja Adie, Kirsty Bond, Abhijit Mate, Jo Skewes, Ali James, Carolyn Brodie, Matthew Johnson, Linda Allsop, Emma Driver, Karina Harris, Mark Drake, Sam Ellis, Bev Maund, Emma Thomas, Kimberley Moore, Matthew Burn, Adam Hamilton, Shageetha Mahalingam, Amulya Misra, Farrah Reid, Adrienne Benford, Derek Hilton, Lorraine Hazell, Keziah Ofori, Anne Louise Thomas, Moncy Mathew, Sonia Dayal, Iona Burn, Kenneth Fotherby, Karla Jennings-Preece, Angela Willberry, Debbie Morgan, Donna Butler, Gurminder Sahota, Kelly Kauldhar, Nasar Ahmad, Angela Stevens, Saugata Das, David Bruce, Yogish Pai, Khin Nyo, Lynsey Stephenson, Richard Nendick, Gill Rogers, Mahesh Dhakal, Sofia Dima, Ellen Brown, Susan Clayton, Penny Gamble, Muhammad Naeem, Rachel Hayman, Rachel Burnip, Philip Earnshaw, David Hargroves, Barbara Ransom, Hannah Rudenko, Ibrahim Balogun, Kirsty Griffiths, Kim Mears, Tom Webb, Linda Cowie, Tessa Hammond, Audrey Thomson, Daniela Ceccarelli, Navraj Chattha, Eva Beranova, Anna Verrion, Andrew Gillian, Natasha Schumacher, Anna Bahk, Susannah Walker, Vera Cvoro, Nicola Chapman, Susan Pound, Rebecca Cain, Sean Mcauley, Mandy Couser, Maria Simpson, Athan Tachtatzis, Khalil Ullah, Don Sims, Rachael Jones, Jonathan Smith, Rebecca Tongue, Mark Willmot, Claire Sutton, Edward Littleton, Jattinder Khaira, Susan Maiden, James Cunningham, Carole Green, Yin-May Chin, Michelle Bates, Katherine Ahlquist, Ingrid Kane, Joanna Breeds, Tenesa Sargent, Laura Latter, Alexandra Pitt Ford, Nicola Gainsborough, Tom Levett, Philip Thompson, Emma Barbon, Angela Dunne, Simon Hervey, Suzanne Ragab, Tracy Sandell, Christine Dickson, Judith Dube, Sharon Power, Nick Evans, Beverley Wadams, Savina Elitova, Beth Aubrey, Tatiana Garcia, James Mcilmoyle, Carol Jeffs, Christina Dickinson, Anis Ahmed, Sanjeev Kumar, Julie Frudd, Charlotte Armer, Andrew Potter, Stacey Donaldson, Joanne Howard, Kirsty Jones, Saikat Dhar, David Collas, Saul Sundayi, Lynn Denham, Deepali Oza, Elaine Walker, Mohit Bhandari, Sissy Ispoglou, Rachel Evans, Kamel Sharobeem, Elaine Walton, Steven Shanu, Anne Hayes, Jennifer Howard-Brown, Steven Billingham, Nic Weir, Vanessa Pressly, Emma Wood, Gabriella Howard, Holly Burton, Pam Crawford, Shuna Egerton, Sue Evans, Jasmine Hakkak, Janet Andrews, Rebecca Lampard, Christopher Allen, Ashleigh Walters, Rasha Said, James Richard Marigold, Sau-Mon Tsang, Robyn Creeden, Chloe Cox, Simon Smith, Imogen Gartrell, Fiona Smith, Colin Jenkins, Joanna Pryor, Andrew Hedges, Fiona Price, Linda Moseley, Lily Mercer, Claire Hughes, Abul Azim, Julie White, Milena Krasinska-Chavez, Shaun Chaplin, James Curtis, Deepwant Singh, Javed Imam, Anne Nicolson, Sajid Alam, Simon Whitworth, Lisa Wood, Elizabeth Warburton, Siobhan Kelly, Joanne Mcgee, Hugh Markus, Denish Chandrasena, Derek Hayden, Juliana Sesay, Helen Hayhoe, Mark Bolton, Jane Macdonald, Jenny Mitchell, Charlotte Farron, Elaine Amis, Diana Day, Ainsley Culbert, Ailene Espanol, Niamh Hannon, Dominic Handley, Sarah Finlay, Sarah Crisp, Lynne Whitehead, Jobbin Francis, Janice Oconnell, Emily Osborne, Rod Beard, Ramesh Krishnamurthy, Langanani Mokoena, Naweed Sattar, Min Myint, Michelle Edwards, Andrew Smith, Paul Corrigan, Anthony Byrne, Joanne Blackburn, Caroline Mcghee, Amanda Smart, Fiona Donaldson, Claire Copeland, Jill Wilson, Rhona Scott, Paul Fitzsimmons, Paula Lopez, Mark Wilkinson, Aravindakshan Manoj, Penelope Cox, Leona Trainor, Glyn Fletcher, Lisa Denny, Karen Kavanagh, Hannah Allsop, Hedley Emsley, Sulaiman Sultan, Alison Mcloughlin, Benjamin Walmsley, Louise Hough, Shakeel Ahmed, Donna Doyle, Bindu Gregary, Sonia Raj, Kirubananthan Nagaratnam, Neelima Mannava, Nyla Haque, Norma Shields, Kate Preston, Geraldine Mason, Kirsty Short, Gemma Lumsdale, Giulia Uitenbosch, Ugnius Sukys, Stacey Valentine, David Jarrett, Kerry Dodsworth, Mary Wands, Nisa Khan, Jane Tandy, Catrin Watkinson, Wendy Golding, Rebecca Butler, Max Williams, Yasmin Davies, Keith Yip, Claire James, Anne Suttling, Aditya Maney, Giles Edward Gamble, Adam Hague, Bethan Charles, Sujata Blane, Beatriz Duran, Caroline Lambert, Katherine Stagg, Robert Whiting, Jane E Homan, Sarah Brown, Malik Hussain, Miriam Harvey, Libby Graham, Leanne Foote, Catherine Lane, Liz (Joan) Kemp, Joy Rowe, Helen Durman, Jayne Foot, Lucy Brotherton, Nicholas Hunt, Corinne Pawley, Alison Whitcher, Patrick Sutton, Susan Mcdonald, Denys Pak, Alison Wiltshire, Jennifer Jagger, Anthony K Metcalf, Gail Louise Healey, Joyce Balami, Clare Marie Self, Melissa Crofts, Annie Chakrabarti, Chit Hmu, Garth Ravenhill, Charmaine Grimmer, Thandar Soe, Jocelyn Keshet-Price, Margaret Langley, Ian Potter, Pui-Lin Tam, Mary Joan Macleod, Patricia Cooper, Michael Christie, Janice Irvine, Faye Annison, David Christie, Celia Meneses, Amber Johnson, Anu Joyson, Sandra Nelson, Vicky Taylor, John Reid, Rebecca Clarke, Jacqueline Furnace, Heather Gow, Youssif Abousleiman, Tania Beadling, Sally Collins, Stuart Jones, Jessica Purcell, Samantha Bloom, Shelly Goshawk, Marcial Landicho, Sivatharshini Sangaralingham, Yasmin Begum, Sherree Mutton, Elangovan Munuswamy Vaiyapuri, Jane Allen, Jemma Lowe, Martin Hughes, Ivan Wiggam, Sarah Cuddy, Suzanne Tauro, Brian Wells, Azlisham Mohd Nor, Nicola Persad, Maggie Kalita, Stuart Weatherby, Claire Brown, Adrian Pace, Daniel Lashley, Mike Marner, Marie Weinling, Natasha Wilmshurst, Darren Waugh, Anna Mucha, Alex Shah, John Baker, Jacqueline Westcott, Richard Cowan, Evangelos Vasileiadis, Samira Mumani, Anthea Parry, Cathy Mason, Melinda Holden, Katerina Petrides, Tomoko Nishiyama, Hina Mehta, Manju Krishnan, Dacey Lynne, Lisa Thomas, Connor Lynda, Catherine Hughes, Clare Clements, Rhys Williams, Tal Anjum, Storton Sharon, Susan Tucker, Paul Jones, Deanne Colwill, Helen Thompson Jones, Dinesh Chadha, Mark Fairweather, Deborah Walstow, Rosanna Fong, Stuart Johnston, Christine Almadenboyle, Sarah Ross, Shona Carson, Priya Nair, Emily Tenbruck, Mairi Stirling, Aparna Pusalkar, Hannah Beadle, Kelly Chan, Puneet Dangri, Asaipillai Asokanathan, Anita Rana, Sunita Gohil, Mark Massyn, Prabhu Aruldoss, Angela Cook, Karen Crabtree, Sura Dabbagh, Toby Black, Caroline Clarke, Denise Mead, Ruth Fennelly, Alpha Anthony, Linda Nardone, Victoria Dimartino, Michele Tribbeck, David Broughton, Dinesh Tryambake, Lynn Dixon, Agnieszka Skotnicka, Jane Thompson, Sarah Whitehouse, Andrew Sigsworth, Jason Wong, Arunkumar Annamalai, Julie Pagan, Brendan Affley, Caroline Sunderland, Lynda Goldenberg, Atif Khan, Peter Wilkinson, Raad Nari, Lucy Abbott, Emma Young, Amritpal Shakhon, Sally Lock, Jack Stewart, Rita Pereira, Margaret Dsouza, Sally Dunn, Anne-Marie Mckenna, Nina Cron, Michelle Kidd, Grace Hull, Kerry Bunworth, Graham Drummond, Karim Mahawish, Nicola Hayes, Lynne Connell, Jennifer Simpson, Helen Penney, Shuja Punekar, Joanne Nevinson, William Wareing, Jacqueline Ward, Richard Greenwood, Duncan Austin, Azra Banaras, Carolin Hogan, Thomas Corbett, Nnebuife Oji, Emma Elliott, Maria Brezitski, Nathalie Passeron, Laura Howaniec, Caroline Watchurst, Krishna Patel, Renuka Erande, Rahi Shah, Nabarun Sengupta, Maria Metiu, Celia Gonzalez, Sarah Funnell, Jordi Margalef, Gillian Peters, Indra Chadbourn, Ramachandran Sivakumar, Rajesh Saksena, Jane Ketley-O'donel, Richard Needle, Elaine Chinery, Alison Wright, Sue Cook, Joseph Ngeh, Harald Proeschel, Paige Cook, Pauline Ashcroft, Simon Sharpe, Stephanie Jones, Damian Jenkinson, Deborah Kelly, Holly Bray, Gunaratnam Gunathilagan, Sally Jones, Sorrell Tilbey, Saidu Abubakar, Joseph Vassallo, Dee Leonard, Lucy Orrell, Aziz Hasan, Asif Khan, Sulmaaz Qamar, Susan Graham, Emma Hewitt, Jennifer Awolesi, Muhammad Haque, Alissa Kent, Elizabeth Bradshaw, Martin Cooper, Inez Wynter, Anoja Rajapakse, Joumana Janbieh, Abu M Nasar, Lynne Wade, Linda Otter, Steve Haigh, Jamie-Rae Burgoyne, Rebecca Boulton, Andrew Boulton, Rayessa Rayessa, Emma Clarkson, Horne Rhian, Amy Fleming, Kim Mitchelson, Vicki Lowthorpe, Ahmed Abdul-Hamid, Phil Jones, Claire Duggan, Abigail Hynes, Emma Nurse, Syed Abid Raza, Sarah Jones, Udaya Pallikona, Bleddyn Edwards, Geraint Morgan, Kirsty Dennett, Helen Tench, Ronda Loosley, Toby Trugeon-Smith, Rhian Jones, Richard Williams, Donna Robson, Sunanda Mavinamane, Sanjeevi Meenakshisundaram, Lalitha Ranga, Sharon Dealing, Andrew Hill, Margaret Hargreaves, Tom Smith, Julie Bate, Linda Harrison, Ramanathan Kirthivasan, Emma Cannon, Joanne Topliffe, Rebecca Keskeys, Sarah Williams, Fiona Mcneela, Frances Cairns, Thomas James, Amanda Lyle, Sheela Shah, George Zachariah, Lauren Fergey, Susan Smolen, Lucy Cooper, Elizabeth Bohannan, Siddiq Omer, Sageet Amlani, Nadia Hunter, Melissa Hawkes-Blackburn, Giosue Gulli, Alice Peacocke, Justine Amero, Maria Burova, Ottilia Speirs, Steph Levy, Lynda Francis, Susan Holland, Sean Brotheridge, Helen Lyon, Christine Hare, Samantha Jackson, Lorraine Stephenson, Samer Al Hussayni, James Featherstone, Agness Bwalya, Arun Singh, M N Goorah, Jamie Walford, Angela Bell, Christine Kelly, Darren Rusk, Deborah Sutton, Farzana Patel, Stephen Duberley, Kathryn Hayes, Lorraine Hunt, Ahmed El Nour, Sacha Honour, Chloe Box, Simon Dyer, Lynne Brown, Kerry Elliott, Emma Temlett, John Paterson, Rosie Furness, Shelli Young, Enoch Orugun, Chris Brewer, Sarah Thornthwaite, Hannah Crowther, Rachel Glover, Moe Sein, Kashif Haque, Elspeth Gibson, Sam Wong, Karen Rotchell, Karen Burton, Lisa Brookes, Linda Bailey, Chris Lindley, Abbi Murray, Karen Waltho, Maureen Holland, Pradeep Kumar, Purnima Harlekar, Laura Booth, Charlotte Culmsee, Jade Drew, Mohammad Khan, Nicola Mackenzie, Carmel Thomas, Jane Ritchie, James Barker, Michael Haley, Donna Cotterill, Lynne Lane, Christine Little, Dawn Simmons, Glenn Saunders, Harvey Dymond, Sarah Kidd, Rachel Warinton, Yara Neves-Silva, Branimir Nevajda, Michael Villaruel, Udayaraj Umasankar, Seema Patel, Anna Man, Natasha Christmas, Ravi Rangasamy, Richard Ladner, Georgina Butt, Wilson Alvares, Narasimha Gadi, Michael Power, Belinda Wroath, Kevin Dynan, David Wilson, Sarah Crothers, Catherine Leonard, Samantha Hagan, Geraldine Douris, Djamil Vahidassr, Alastair Thompson, Brian Gallen, Shirley Mckenna, Collette Edwards, Clare Mcgoldrick, Murdi Bhattad, Khalil Kawafi, Deborah Morse, Patricia Jacob, Lisa Turner, Narayanamoorti Saravanan, Linda Johnson, Sadie Humphrey, Robert Namushi, Ramesh Patel, Jemma Mclaughlin, Paul Omahony, Esther Osikominu, Chukwuka Orefo, Chisha Mcdonald, Esther Makanju, Tabindah Khan, Grace Appiatse, Helena Stone, Martia Augustin, Alicia Wardale, Maqsud Salehin, Duncan Bailey, Luciano Garcia-Alen, Latheef Kalathil, Sarah Tinsley, Taya Jones, Kelly Amor, Andrew Ritchings, Emma Margerum, Jane Horton, Richard Miller, Nireekshana Gautam, Julie Meir, Amaryl Jones, Janet Putteril, Mirella Lepore, Rachel Gallifent, Laura-Louise Arundell, Catherine Mcredmond, Alicia Goulding, Vivek Nadarajan, Julia Laurence, Su Fung Lo, Sabina Melander, Paul Nicholas, Elizabeth Woodford, Gillian Mckenzie, Vietland Le, Jacolene Crause, Robert Luder, Maneesh Bhargava, Girish Bhome, Venetia V Johnson, Dara Chesser, Hayley Bridger, Elodie Murali, Jon Scott, Susan Morrison, Amy Burns, Julie Graham, Madeline Duffy, Khalid Ali, Emma Pitcher, Jane Gaylard, Julie Newman, Sunil Punnoose, Sarah Besley, Kirtan Purohit, Amy Rees, Mark Davy, Osman Chohan, Muhammad Fozan Khan, Rachel Walker, Vicky Murray, Charlotte Bent, Susan Oakley, Cassilda Peixoto, Suzanne Jones, Gaybrielle Livingstone, Fiona Butler, Sally Bradfield, Laura Gordon, Jenneke Schmit, Anika Wijewardane, Tineke Edmunds, Rebecca Wills, Catherine Medcalf, Lucia Argandona, Larissa Cuenoud, Hanna Hassan, Esther Erumere, Aidan Ocallaghan, Patrick Gompertz, Ozlem Redjep, Grace Auld, Anna Song, Tillana Tarkas, Hashim Kabash, Rumbi Hungwe, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Population and Behavioural Science Division, and University of St Andrews. School of Medicine

Subjects
RM, medicine.medical_specialty, Neurology, Neurologi, NDAS, 030204 cardiovascular system & hematology, Placebo, Minimisation (clinical trials), Article, B700, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, Modified Rankin Scale, law, Fluoxetine, Internal medicine, Humans, Medicine, 030212 general & internal medicine, R2C, Acute stroke, business.industry, ~DC~, General Medicine, Odds ratio, RM Therapeutics. Pharmacology, Stroke, RC Internal medicine, BDC, business, Selective Serotonin Reuptake Inhibitors, RC, medicine.drug
Abstract

Background: Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.Methods: FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.Findings: Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months.Interpretation: Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.Funding: UK Stroke Association and NIHR Health Technology Assessment Programme.

Published
2019
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8. Pulmonary hypertension-targeted therapies in heart failure: A systematic review and meta-analysis

Author

Sébastien Bonnet, Yves Lacasse, Jean-Christophe Lega, Caroline Lambert, Louis-Vincent Morin-Thibault, Steeve Provencher, and Charles-Antoine Guay

Subjects
Respiratory System Agents, lcsh:Medicine, 030204 cardiovascular system & hematology, Cochrane Library, law.invention, 0302 clinical medicine, Mathematical and Statistical Techniques, Randomized controlled trial, law, Medicine and Health Sciences, 030212 general & internal medicine, lcsh:Science, Diuretics, Multidisciplinary, Ejection fraction, Pharmaceutics, Standard treatment, Statistics, Drugs, Hematology, Metaanalysis, Research Assessment, Exercise Therapy, Meta-analysis, Physical Sciences, Research Article, medicine.medical_specialty, Systematic Reviews, Death Rates, Hypertension, Pulmonary, Cardiology, Research and Analysis Methods, 03 medical and health sciences, Complementary and Alternative Medicine, Drug Therapy, Population Metrics, Internal medicine, medicine, Humans, Statistical Methods, Heart Failure, Pharmacology, Population Biology, business.industry, lcsh:R, Hemodynamics, Biology and Life Sciences, Phosphodiesterase 5 Inhibitors, medicine.disease, Pulmonary hypertension, Discontinuation, Physical Fitness, Heart failure, lcsh:Q, business, Receptor Antagonist Therapy, Mathematics
Abstract

Background Pulmonary hypertension (PH) due to left heart failure (HF) is the most common form of PH. However, treatment is unclear because there are conflicting results about safety and efficacy of PH-targeted therapies. Objectives To assess the effects of PH-targeted therapy on exercise capacity in HF patients. Methods MEDLINE, EMBASE and the Cochrane Library were searched from January 1990 to July 2017 for randomized controlled trials comparing PH-targeted therapies to conventional therapy in HF. The primary outcome was to assess the effects on exercise capacity. Secondary outcomes included mortality, hospitalisation, NT-proBNP levels, echocardiographic and hemodynamics parameters and discontinuation rate. Results 22 studies were included (n = 5448), including 3, 8 and 11 studies with low, high and unknown risk of bias, respectively. PH-targeted therapies were associated with an improvement of exercise capacity (standardized mean difference 0.29;95%CI:0.08-0.50, p = 0.006). Pre-specified subgroup analyses found that this improvement was predominantly observed in studies evaluating phosphodiesterase-5 inhibitors and prostanoids and in patients with reduced ejection fraction. Moreover, systolic pulmonary artery pressure measured by echocardiography was improved (mean difference: -7.5mmHg; [95%CI]: -14.9,-0.1, p = 0.05), which was also entirely driven by studies evaluating phosphodiesterase-5 inhibitors. However, PH-targeted therapies were associated with an increased treatment discontinuation rates and a potential increase in mortality compared to standard treatment. Conclusions In conclusion, PH-targeted therapies and especially phosphodiesterase-5 inhibitors may improve exercise capacity in patients with HF. However, an increase in adverse outcomes was likely. Moreover, most studies were at high or unknown risk of bias, precluding confident conclusions about the effects of PH-targeted therapies.

Published
2018

9. Peripheral and local predictive immune signatures identified in a phase II trial of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV melanoma

Author

Alan Spatz, Huy Le, Shirin Kazemi, Jida El-Hajjar, Jennifer Elisabeth Friedmann, Pamela Thebault, Jean-Pierre M. Ayoub, Jean-François Cailhier, Léon C van Kempen, Eftihia Cocolakis, Rahima Jamal, Jeanne Dionne, Karl Belanger, Réjean Lapointe, Caroline Lambert, and Wilson H. Miller

Subjects
Male, 0301 basic medicine, Oncology, Neuroblastoma RAS viral oncogene homolog, Cancer Research, Skin Neoplasms, Immune score, medicine.medical_treatment, Carboplatin/pharmacology, Carboplatin, chemistry.chemical_compound, 0302 clinical medicine, Ipilimumab/pharmacology, Antineoplastic Combined Chemotherapy Protocols, PD-1, Skin Neoplasms/drug therapy, Immunology and Allergy, Medicine, Melanoma/drug therapy, Melanoma, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Paclitaxel/pharmacology, Treatment Outcome, 030220 oncology & carcinogenesis, Molecular Medicine, Female, Immunotherapy, Chemokines, Research Article, medicine.drug, Adult, medicine.medical_specialty, Paclitaxel, Predictive Biomarkers, Immunology, Ipilimumab, Antineoplastic Combined Chemotherapy Protocols/pharmacology, lcsh:RC254-282, 03 medical and health sciences, Immune system, Internal medicine, Humans, Chemotherapy, Adverse effect, Aged, Neoplasm Staging, Pharmacology, business.industry, medicine.disease, 030104 developmental biology, chemistry, business, B lymphocytes
Abstract

Background Checkpoint blockade with ipilimumab provides long-term survival to a significant proportion of patients with metastatic melanoma. New approaches to increase survival and to predict which patients will benefit from treatment are needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP) to assess its safety, efficacy, and to search for peripheral and tumor-based predictive biomarkers. Methods Thirty patients with untreated unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse events (AEs) were monitored and response to treatment was evaluated. Tumor tissue and peripheral blood were collected at specified time points to characterize tumor immune markers by immunohistochemistry and systemic immune activity by multiplex assays and flow cytometry. Results Eighty three percent of patients received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed. Best Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%, respectively. Median overall survival was 16.2 months. Response to treatment was positively correlated with a higher tumor CD3+ infiltrate (immune score) at baseline. NRAS and BRAF mutations were less frequent in patients who experienced clinical benefit. Assessment of peripheral blood revealed that non-responders had elevated baseline levels of CXCL8 and CCL4, and a higher proportion of circulating late differentiated B cells. Pre-existing high levels of chemokines (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly associated with worse patient overall survival. Elevated proportions of circulating CD8+/PD-1+ T cells during treatment were associated with worse survival. Conclusions The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment. A pre-existing systemic inflammatory state characterized by elevation of selected chemokines and advanced B cell differentiation, was strongly associated with poor patient outcomes, revealing potential predictive circulating biomarkers. Trial registration Clinicaltrials.gov, NCT01676649, registered on August 29, 2012. Electronic supplementary material The online version of this article (10.1186/s40425-017-0290-x) contains supplementary material, which is available to authorized users.

Published
2017
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10. Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH

Author

Sandra N Bonnet, Roxane Paulin, Eve Tremblay, Maria Jacob, Audrey Courboulin, Steeve Provencher, Marjorie Barrier, Caroline Lambert, Véronique Tremblay, Tanya Perreault, Pierre Bonnet, and Sébastien Bonnet

Subjects
Male, Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Cardiotonic Agents, Hypertension, Pulmonary, Apoptosis, Bone Morphogenetic Protein Receptors, Type II, Muscle, Smooth, Vascular, chemistry.chemical_compound, Proliferating Cell Nuclear Antigen, In Situ Nick-End Labeling, Animals, Humans, Medicine, Familial Primary Pulmonary Hypertension, STAT3, Transcription factor, Cells, Cultured, Cell Proliferation, rho-Associated Kinases, NFATC Transcription Factors, biology, Interleukin-6, business.industry, NFAT, Plumbagin, medicine.disease, Pulmonary hypertension, Rats, BMPR2, chemistry, Potassium Channels, Voltage-Gated, STAT protein, biology.protein, Cancer research, Calcium, business, Naphthoquinones
Abstract

Like cancer, pulmonary arterial hypertension (PAH) is characterised by a pro-proliferative and anti-apoptotic phenotype. In PAH, pulmonary artery smooth muscle cell (PASMC) proliferation is enhanced and apoptosis suppressed. The sustainability of this phenotype requires the activation of pro-survival transcription factors, such as signal transducer and activator of transcription (STAT)3 and nuclear factor of activated T-cells (NFAT). There are no drugs currently available that are able to efficiently and safely inhibit this axis. We hypothesised that plumbagin (PLB), a natural organic compound known to block STAT3 in cancer cells, would reverse experimental pulmonary hypertension. Using human PAH-PASMC, we demonstrated in vitro that PLB inhibits the activation of the STAT3/NFAT axis, increasing the voltage-gated K(+) current bone morphogenetic protein receptor type II (BMPR2), and decreasing intracellular Ca(2+) concentration ([Ca(2+)](i)), rho-associated coiled-coil containing protein kinase (ROCK)1 and interleukin (IL)-6, contributing to the inhibition of PAH-PASMC proliferation and resistance to apoptosis (proliferating cell nuclear antigen (PCNA), TUNEL, Ki67 and anexine V). In vivo, PLB oral administration decreases distal pulmonary artery remodelling, mean pulmonary artery pressure and right ventricular hypertrophy without affecting systemic circulation in both monocrotaline- and suden/chronic hypoxia-induced PAH in rats. This study demonstrates that the STAT3/NFAT axis can be therapeutically targeted by PLB in human PAH-PASMC and experimental PAH rat models. Thus, PLB could be considered a specific and attractive future therapeutic strategy for PAH.

Published
2012
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11. HIF-1 inhibition decreases systemic vascular remodelling diseases by promoting apoptosis through a hexokinase 2-dependent mechanism

Author

Geneviève A. Robitaille, Darren E. Richard, Caroline Lambert, M. Roy, and Sébastien Bonnet

Subjects
Male, medicine.medical_specialty, Vascular smooth muscle, Physiology, medicine.medical_treatment, Myocytes, Smooth Muscle, Down-Regulation, Apoptosis, Mitochondrion, Transfection, Muscle, Smooth, Vascular, Vascular remodelling in the embryo, Rats, Sprague-Dawley, Glycogen Synthase Kinase 3, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, Hexokinase, Physiology (medical), Internal medicine, medicine, Animals, Humans, Carotid Stenosis, Glycolysis, Cells, Cultured, PI3K/AKT/mTOR pathway, Cell Proliferation, Membrane Potential, Mitochondrial, Platelet-Derived Growth Factor, Glycogen Synthase Kinase 3 beta, biology, Growth factor, Hypoxia-Inducible Factor 1, alpha Subunit, Mitochondria, Muscle, Rats, Cell biology, Disease Models, Animal, Endocrinology, chemistry, biology.protein, RNA Interference, Cardiology and Cardiovascular Medicine, Proto-Oncogene Proteins c-akt, Platelet-derived growth factor receptor
Abstract

Aims Vascular remodelling diseases are characterized by the presence of proliferative and apoptosis-resistant vascular smooth muscle cells (VSMC). There is evidence that pro-proliferative and anti-apoptotic states are characterized by metabolic remodelling (a glycolytic phenotype with hyperpolarized mitochondria) involving Akt pathway activation by circulating growth factors. Hypoxia-inducible factor-1 (HIF-1) is involved in different vascular diseases. Since this transcription factor is implicated in metabolic responses, we hypothesized that HIF-1 activity could be involved in vascular remodelling in response to arterial injury. Methods and results Our findings indicate that growth factors, such as platelet-derived growth factor (PDGF), activate the Akt pathway (measured by immunoblot) in human carotid artery VSMC. Activation of this pathway increased HIF-1 activation (measured by immunoblot), leading to increased glycolysis in VSMC. Expression and mitochondrial activity of hexokinase 2 (HXK2), a primary initiator of glycolysis, are increased during HIF-1 activation. The mitochondrial activity of HXK2 in VSMC led to the hyperpolarization of mitochondrial membrane potential (measured by tetramethylrhodamine methyl-ester perchlorate) and the suppression of apoptosis (measured by TUNEL assay and 3 activity), effects that are blocked by HIF-1 inhibition. Additionally, HIF-1 inhibition also decreased VSMC proliferation (proliferating cell nuclear antigen and Ki-67 assays). In vivo , we demonstrate that localized HIF-1 inhibition, using a dominant-negative HIF-1α adenoviral construct, prevented carotid artery post-injury remodelling in rats. Conclusion We propose that HIF-1 is centrally involved in carotid artery remodelling in response to arterial injury and that localized inhibition of HIF-1 may be a novel therapeutic strategy to prevent carotid stenosis.

Published
2010
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12. Systemic immune signature of inflammation in metastatic melanoma (MM) patients treated with ipilimumab (IPI) and carboplatin/paclitaxel (CP)

Author

Alan Spatz, Rahima Jamal, Jennifer Elisabeth Friedmann, Jean-François Cailhier, Jeanne Dionne, Pamela Thebault, Huy Le, Léon C van Kempen, Karl Belanger, Réjean Lapointe, Jean-Pierre M. Ayoub, Stéphanie Lepage, Eftihia Cocolakis, Caroline Lambert, Shirin Kazemi, Jida El Hajjar, and Wilson H. Miller

Subjects
Cancer Research, medicine.medical_specialty, Chemokine, biology, business.industry, T cell, Inflammation, Ipilimumab, Gastroenterology, Immune system, medicine.anatomical_structure, Oncology, Internal medicine, medicine, biology.protein, medicine.symptom, Neutrophil to lymphocyte ratio, business, CD8, B cell, medicine.drug
Abstract

185 Background: Only a subset of MM patients benefit from treatment with IPI. In an effort to increase response and identify predictive immune biomarkers, we combined IPI with CP. We here report a significant correlation between overall survival (OS) and biomarkers of a pre-existing inflammatory state. Methods: 30 patients were treated with C (AUC = 6) and P (175mg/m2) every 3 weeks x 5 and IPI (3mg/kg) every 3 weeks x 4. Blood was collected throughout. OS Kaplan–Meier curves were compared by the log-rank test. Cutoff thresholds defining high or low levels of chemokines, B cell populations and PD-1+CD8+ T cell populations were established from the mean value of a given variable from all patients. Neutrophil to Lymphocyte Ratio (NLR) and Systemic Immune Inflammation Index defined as Platelet x Neutrophil to Lymphocyte Ratio (SII) were calculated at baseline and tested for association with OS. SII ≥ 1375 and NLR ≥ 5 were considered as high risk groups. Results: Median OS was 16.2 months, with a 3-year OS of 36.7% for all patients. High levels of CCL3 (HR = 2.79, p = 0.0159), CCL4 (HR = 8.36, p < 0.0001) and CXCL8 (HR = 3.52, p = 0.0037) were associated with worse OS. Advanced B cell differentiation before treatment was associated with worse patient outcomes. High levels of early differentiated Bm2 ( > 57%) were strongly associated with better OS: HR = 0.26 p = 0.004 whereas high eBm5+Bm5 ( > 14%) levels were strongly associated with worse OS: HR = 2.65, p = 0.029. Patients with higher proportions of PD-1+CD8+ T cells in circulation during treatment had poorer OS (HR = 3.84, p = 0.004) at week 10; (HR = 3.53, p = 0.005) at week 13 and (HR = 2.84, p = 0.040) at week 24. High risk SII (HR = 3.30, p = 0.0192) and NLR (HR = 2.367, p = 0.0486) were associated with worse OS. Conclusions: We have identified a significant correlation between pre-existing systemic inflammatory state and a poor response to IPI and CP. Specifically elevated CCL3, CCL4 and CXCL8, baseline B lymphocyte subset skewing, increased CD8+PD-1+ T lymphocytes, increased NLR and SII were all strongly associated to worse OS. Comprehensive immune monitoring provides evidence for new circulating biomarkers predicting outcome in MM patients treated with IPI and CP. Clinical trial information: NCT01676649.

Published
2018
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13. Immune biomarker correlates from a Phase II study of ipilimumab (IPI) with carboplatin and paclitaxel (CP) in patients with unresectable stage III or IV metastatic melanoma (MM)

Author

Réjean Lapointe, Jennifer Elisabeth Friedmann, Jeanne Dionne, Karl Belanger, Pamela Thebault, Alan Spatz, Huy Le, Jean-François Cailhier, Cecile Grange, Rahima Jamal, Jean-Pierre M. Ayoub, Eftihia Cocolakis, Caroline Lambert, Shirin Kazemi, Wilson H. Miller, and Léon C van Kempen

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Immunology, Phases of clinical research, Ipilimumab, Bioinformatics, chemistry.chemical_compound, Immune system, hemic and lymphatic diseases, Internal medicine, medicine, Immunology and Allergy, In patient, Stage (cooking), Pharmacology, business.industry, Carboplatin, chemistry, Paclitaxel, Poster Presentation, Molecular Medicine, Biomarker (medicine), business, medicine.drug
Abstract

Meeting abstracts Pivotal studies with anti-CTLA-4 (Ipilimumab or IPI) demonstrated increased overall survival (OS) both as single agent (10.1 months) and with DTIC (11.2 months). We've previously reported an encouraging safety profile with IPI plus CP and early efficacy results. We now report

Published
2015
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14. Abstract CT098: Phase 1 first-in-human study of anti-clusterin antibody AB-16B5 in patients with advanced solid malignancies

Author

Alan Spatz, Caroline Lambert, Jacques Jolivet, Gerald Batist, Mario C. Filion, Léon C van Kempen, Adrian Langleben, Oksana Markova, Julie Laurin, and Cristiano Ferrario

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, business.industry, Nausea, Melanoma, Cancer, medicine.disease, Gastroenterology, Metastasis, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, Tolerability, 030220 oncology & carcinogenesis, Internal medicine, Medicine, Sarcoma, Bone marrow, medicine.symptom, business, Follicular thyroid cancer
Abstract

Background. Secreted clusterin (sCLU) promotes survival and stimulates epithelial to mesenchymal transition (EMT) in cancer cells, leading to tumor invasion, metastasis and chemoresistance. AB-16B5 is a humanized IgG2 mAb specific for the EMT-inducing region in some isoforms of sCLU produced by tumor cells, with much less affinity for sCLU found in healthy individuals. Pre-clinical models showed that AB-16B5 inhibits EMT and displays synergy with chemotherapeutic agents. We performed a first-in-human phase I trial to assess safety and tolerability of AB-16B5 and to determine a recommended dose for phase II studies. Methods. Patients (pts) with evaluable and refractory advanced solid malignancies were eligible with adequate organ and bone marrow functions and an ECOG of 0-2. AB-16B5 was administered as a 60-min IV weekly infusion (21-day cycles). Dose escalation followed an accelerated scheme for the 1.5 and 3 mg/kg dose levels and a standard 3 + 3 design for subsequent levels (6, 9 and 12 mg/kg). All pts underwent collection of blood samples for PK analysis. Pre-treatment and post-treatment (end of cycle 2) tumor biopsies were collected if feasible in pts dosed at 9 and 12 mg/kg. Biopsies were used to evaluate EMT status and to investigate the presence of AB-16B5. Radiological imaging was performed every 6 weeks for the first 8 cycles, then every 9 weeks thereafter. Results. 15 pts (13 carcinomas of various origins, 1 melanoma and 1 sarcoma) were enrolled from May 2015 to October 2016. Pts received between 1 and 53 weekly doses (median: 9 doses). The most frequently reported adverse events (AEs, all causalities) were nausea, abdominal pain, constipation, vomiting, back pain, pruritus and dyspnea. Most of the AEs were of Grade 1 or 2. Among the AEs ≥ Grade 3, only 2 (Grade 3 infusion related reaction and rash) were judged related to AB-16B5. No dose-limiting toxicities were identified during the first cycle of treatment for any pt. 5 serious AEs were reported (sepsis, pyrexia, dyspnea, intra-abdominal hemorrhage and main stem bronchus obstruction), none of which were judged related to the study treatment. PK analysis across all dose levels confirmed that systemic exposure to AB-16B5 increased in a dose proportional manner. The presence of AB-16B5 at the tumor site was confirmed in all 5 pts where a post-treatment tumor lysate could be generated. Biomarker analysis in paired tumor biopsies provided some evidence for EMT inhibition as seen by increased E-cadherin expression after treatment with AB-16B5 in 2 pts. In one of these 2 pts with advanced gastric cancer, this was also accompanied by a loss of vimentin expression. This pt had stable disease (SD) with clinical benefit and remained on treatment for 24 weeks. Another pt with follicular thyroid cancer had SD for almost 1 year. Conclusion. Weekly infusions of AB-16B5 are well tolerated up to 12 mg/kg. This dose level is the recommended phase II dose for future trials. Early correlative studies on tumor tissue provide evidence of molecular modulation of the tumor environment in humans. Clinical trial registry number: NCT02412462 Citation Format: Cristiano Ferrario, Julie Laurin, Leon Van Kempen, Caroline Lambert, Alan Spatz, Oksana Markova, Gerald Batist, Adrian Langleben, Mario Filion, Jacques Jolivet. Phase 1 first-in-human study of anti-clusterin antibody AB-16B5 in patients with advanced solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT098. doi:10.1158/1538-7445.AM2017-CT098

Published
2017
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15. Krüppel-like Factor 5 contributes to pulmonary artery smooth muscle proliferation and resistance to apoptosis in human pulmonary arterial hypertension

Author

Maria Jacob, Véronique Tremblay, Marjorie Barrier, Steeve Provencher, Jolyane Meloche, Sébastien Bonnet, Caroline Lambert, Audrey Courboulin, Mathilde Chapolard, Malik Bisserier, and Roxane Paulin

Subjects
Male, medicine.medical_treatment, 030204 cardiovascular system & hematology, Pulmonary arterial hypertension, Rats, Sprague-Dawley, STAT3, 0302 clinical medicine, Myocyte, Familial Primary Pulmonary Hypertension, Cells, Cultured, 0303 health sciences, biology, Middle Aged, KLF5, 3. Good health, Up-Regulation, Female, Platelet-derived growth factor receptor, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Adolescent, Hypertension, Pulmonary, proliferation, Myocytes, Smooth Muscle, Kruppel-Like Transcription Factors, Immunophenotyping, 03 medical and health sciences, Young Adult, Downregulation and upregulation, Internal medicine, medicine.artery, Survivin, medicine, Animals, Humans, 030304 developmental biology, Cell Proliferation, lcsh:RC705-779, Growth factor, Research, apoptosis, lcsh:Diseases of the respiratory system, medicine.disease, Pulmonary hypertension, Rats, Endocrinology, Pulmonary artery, biology.protein, Apoptosis Regulatory Proteins
Abstract

Background Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation of pulmonary artery smooth muscle cell (PASMC) and suppressed apoptosis. This phenotype has been associated with the upregulation of the oncoprotein survivin promoting mitochondrial membrane potential hyperpolarization (decreasing apoptosis) and the upregulation of growth factor and cytokines like PDGF, IL-6 and vasoactive agent like endothelin-1 (ET-1) promoting PASMC proliferation. Krüppel-like factor 5 (KLF5), is a zinc-finger-type transcription factor implicated in the regulation of cell differentiation, proliferation, migration and apoptosis. Recent studies have demonstrated the implication of KLF5 in tissue remodeling in cardiovascular diseases, such as atherosclerosis, restenosis, and cardiac hypertrophy. Nonetheless, the implication of KLF5 in pulmonary arterial hypertension (PAH) remains unknown. We hypothesized that KLF5 up-regulation in PAH triggers PASMC proliferation and resistance to apoptosis. Methods and results We showed that KFL5 is upregulated in both human lung biopsies and cultured human PASMC isolated from distal pulmonary arteries from PAH patients compared to controls. Using stimulation experiments, we demonstrated that PDGF, ET-1 and IL-6 trigger KLF-5 activation in control PASMC to a level similar to the one seen in PAH-PASMC. Inhibition of the STAT3 pathway abrogates KLF5 activation in PAH-PASMC. Once activated, KLF5 promotes cyclin B1 upregulation and promotes PASMC proliferation and triggers survivin expression hyperpolarizing mitochondria membrane potential decreasing PASMC ability to undergo apoptosis. Conclusion We demonstrated for the first time that KLF5 is activated in human PAH and implicated in the pro-proliferative and anti-apoptotic phenotype that characterize PAH-PASMC. We believe that our findings will open new avenues of investigation on the role of KLF5 in PAH and might lead to the identification of new therapeutic targets.

Published
2011

16. A Standardized Transcutaneous Electric Acupoint Stimulation for Relieving Tobacco Urges in Dependent Smokers

Author

Siew Wan Hee, Audrey S. L. Tan, David Picard, Ji-Sheng Han, Ivan Berlin, Caroline Lambert, and Tat-Leang Lee

Subjects
Smoke, medicine.medical_specialty, education.field_of_study, Traditional medicine, business.industry, medicine.medical_treatment, Population, Stimulation, lcsh:Other systems of medicine, Placebo, medicine.disease, lcsh:RZ201-999, Clinical trial, Complementary and alternative medicine, Internal medicine, Acupuncture, medicine, Smoking cessation, Original Article, education, Nicotine dependence, business, RC
Abstract

The efficacy of acupuncture in smoking cessation, and its effect on the urge to smoke are unclear. We evaluated the effect of a standardized protocol of transcutaneous electric acupoint stimulations (TEAS) on alleviating the urge to smoke. Ninety-eight smokers were recruited in two double-blind studies. Participants abstained from smoking for 26 h, and were randomized to receive TEAS alternating between 2 and 100 Hz at four acupoints (LI4 and PC8, PC6 and TE5) at four different intensities (10, 5, Intermittent 5 or 0 mA). The urge to smoke was assessed by the Questionnaire of Smoking Urges (QSU-Brief). In Experiment 1, the 10 mA group (n= 20) was compared with the 5 mA group (n= 20); the increase in smoking urges did not differ significantly. Considering the possibility that 5 mA may be an active intervention, in Experiment 2, a true placebo (0 mA), and a proxy of placebo [Intermittent 5 mA (i5 mA)] were compared with 10 mA TEAS. In this experiment, 10 mA (n= 20) TEAS showed a tendency to alleviate smoking urges compared with 0 mA (n= 16), and i5 mA (n= 19) TEAS. Only when the data of smokers with Fagerstöm Test for Nicotine Dependence score ≥5 were analyzed that the difference between the 10 mA group and the control group (0 and i5 mA) became significant. Based on these preliminary findings, we conclude that TEAS applied on the skin may antagonize the increase in urge to smoke in abstinent-dependent smokers. It seems warranted to assess the efficacy of TEAS in smoking cessation clinical trials involving a larger population of dependent smokers.

Published
2011

17. Danqi Piantang Jiaonang (DJ), a traditional Chinese medicine, in poststroke recovery

Author

Christopher Chen, Bernard P.L. Chan, David Picard, Marie Germaine Bousser, Caroline Lambert, Edwin Sy Chan, Shi Xuemin, Narayanaswamy Venketasubramanian, and Robert Gan

Subjects
Adult, Male, medicine.medical_specialty, medicine.medical_treatment, Traditional Chinese medicine, law.invention, Randomized controlled trial, Double-Blind Method, law, medicine, Humans, Medicine, Chinese Traditional, Intensive care medicine, Stroke, Cause of death, Aged, Advanced and Specialized Nursing, business.industry, Cerebral infarction, Neuroaid, Recovery of Function, Middle Aged, medicine.disease, Surgery, Clinical trial, Treatment Outcome, Motor Skills, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Stroke recovery, Drugs, Chinese Herbal
Abstract

Background and Purpose— Stroke is a leading cause of death and disability worldwide. Despite improvements in acute stroke treatment, many patients only make a partial or poor recovery. Therefore, there is a need for treatments that would further improve outcome. Danqi Piantang Jiaonang (DJ; NeuroAid), a traditional Chinese medicine widely used in China to improve recovery after stroke, has been compared with another traditional Chinese medicine in 2 unpublished randomized clinical trials. The results of these studies were pooled and reanalyzed to assess efficacy and safety. Methods— Six hundred five subjects were randomized in 2 randomized double-blinded, controlled trials to receive either DJ or Buchang Naoxintong Jiaonang. Subjects were treated for 1 month. Inclusion criteria were: (1) patients with recent (from 10 days to 6 months) ischemic stroke; (2) patients satisfying Western diagnostic standards for stroke and traditional Chinese medicine standards for diagnosis of apoplexy; and (3) Diagnostic Therapeutic Effects of Apoplexy score ≥10. Results— The functional outcome, measured by the Comprehensive Function Score component of the Diagnostic Therapeutic Effects of Apoplexy scale, showed a statistically significant superiority of DJ over the control treatment group (relative risk, 2.4; 95% CI, 1.28 to 4.51; P =0.007). Tolerance was excellent in both groups. Conclusions— The pooled analysis of 2 unpublished trials of DJ, a traditional Chinese medicine currently approved in China to improve neurological recovery after stroke, shows good tolerability and superiority of DJ over another traditional Chinese medicine also approved for stroke. A large double-blind randomized clinical trial is required to further assess the safety and efficacy of DJ.

Published
2009

18. Danqi Piantan Jiaonang does not modify hemostasis, hematology, and biochemistry in normal subjects and stroke patients

Author

Caroline Lambert, Edwin Sy Chan, Marie-Germaine Bousser, Jiao Lianting, Robert Gan, Narayanaswamy Venketasubramanian, Michel Meyer Samama, Bernard P.L. Chan, and Christopher Chen

Subjects
Adult, Male, medicine.medical_specialty, Stroke patient, medicine.medical_treatment, Administration, Oral, Capsules, Traditional Chinese medicine, Cohort Studies, Internal medicine, Medicine, Humans, Medicine, Chinese Traditional, Stroke, Aged, Hemostasis, Hematology, Safety studies, Aspirin, Dose-Response Relationship, Drug, business.industry, Neuroaid, Middle Aged, medicine.disease, Neurology, Emergency medicine, Hemorheology, Physical therapy, Drug Therapy, Combination, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Platelet Aggregation Inhibitors, Drugs, Chinese Herbal
Abstract

Background and Objective: Previous studies on Danqi Piantan Jiaonang (DPJ, NeuroAid®), a traditional Chinese medicine, in stroke patients showed promising results. Our aim was to determine the safety of DPJ in normal subjects and stroke patients through a series of studies assessing its immediate and long-term effects, alone and in combination with aspirin, on hematological, hemostatic, and biochemical parameters. Methods: We conducted 3 studies from December 2004 to May 2006. Study 1 was a case series which recruited 32 healthy volunteers who were given 2 oral doses of 4 DPJ capsules (0.4 g/capsule) 6 h apart. Study 2 was a randomized controlled trial of 22 healthy volunteers who received either 1 oral dose of aspirin 300 mg alone or a combination of 1 dose of aspirin 300 mg and 2 doses of 4 DPJ capsules taken 6 h apart. For both studies 1 and 2, hemostatic parameters (prothrombin time, activated partial thromboplastin time, fibrinogen, platelet aggregation, D-dimer) were tested at baseline, and after 2 and 8 h. Study 3 was a case series which recruited 10 patients with recent ischemic stroke (within 7 days) who were given 4 DPJ capsules taken orally 3 times a day for 1 month. Blood tests for hemostatic, hematological (complete blood count), and biochemical parameters (glucose, creatinine, alanine aminotransferase, aspartate transaminase, C-reactive protein) were performed at baseline, and after 1 and 4 weeks. Results: Apart from the expected changes in platelet aggregation in subjects taking aspirin, no significant differences were detected in hemostatic parameters at baseline, and 2 and 8 h after oral intake of DPJ alone or in combination with aspirin. Likewise, no significant differences were observed in hematological, hemostatic, and biochemical parameters at baseline, and after 1 and 4 weeks of oral intake of DPJ. Conclusion: DPJ does not significantly modify hematological, hemostatic, and biochemical parameters in normal subjects and stroke patients.

Published
2007

19. One-year overall survival (OS) and biomarker correlates from a phase II study of ipilimumab (IPI) with carboplatin and paclitaxel (CP) in patients with unresectable stage III or IV metastatic melanoma (MM)

Author

Réjean Lapointe, Caroline Lambert, Jennifer Elisabeth Friedmann, Jeanne Dionne, Wilson H. Miller, Jean-Pierre M. Ayoub, Rahima Jamal, Jean-François Cailhier, Cecile Grange, Shirin Kazemi, Pamela Thebault, Huy Le, Léon C van Kempen, Alan Spatz, Eftihia Cocolakis, and Karl Belanger

Subjects
Oncology, Cancer Research, medicine.medical_specialty, business.industry, Phases of clinical research, Ipilimumab, Carboplatin, Surgery, chemistry.chemical_compound, chemistry, Paclitaxel, hemic and lymphatic diseases, Internal medicine, Overall survival, Medicine, Biomarker (medicine), In patient, Stage (cooking), business, medicine.drug
Abstract

9062 Background: Pivotal studies with IPI demonstrated increased OS both as single agent (10.1 months) and with DTIC (11.2 months). We’ve previously reported an encouraging safety profile with IPI ...

Published
2015
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20. Corporate governance and profit manipulation: a French field study

Author

Samuel Sponem, Caroline Lambert, Groupement de Recherche et d'Etudes en Gestion à HEC (GREGH), Ecole des Hautes Etudes Commerciales (HEC Paris)-Centre National de la Recherche Scientifique (CNRS), Dauphine Recherches en Management (DRM), Université Paris Dauphine-PSL, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)

Subjects
medicine.medical_specialty, Information Systems and Management, Sociology and Political Science, business.industry, Corporate governance, 05 social sciences, management controllers, corporate governance, Accounting, 050201 accounting, Profit (economics), Positive accounting, field study, 0502 economics and business, Opportunism, profit manipulation, medicine, Economics, [SHS.GESTION]Humanities and Social Sciences/Business administration, profit manipulation,management controllers,corporate governance,field study, business, 050203 business & management, Finance, Legitimacy
Abstract

International audience; Profit manipulation has been largely studied through Positive Accounting Theory (PAT). However, the weakness of the results obtained would suggest using different theoretical and methodological approaches to examine this subject. In France, management controllers play a central role in profit manipulation. This paper offers a comprehensive analysis of their profit manipulation practices. Using results from 32 interviews in 13 companies, we argue that the spread of Anglo-Saxon corporate governance model has fostered such behaviour. Far from the opportunism hypothesis supported by Positive Accounting Theory, profit manipulation is used as a tool by management controllers to gain broader legitimacy within organisations and/or to adopt what they claim to be ethical behaviour.

Published
2005
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21. Searching for Lazarus

Author

Caroline Lambert

Subjects
Government, medicine.medical_specialty, business.industry, Public health, General Engineering, medicine, General Earth and Planetary Sciences, General Medicine, Public administration, business, General Environmental Science
Abstract

South Africa’s public health system is in disarray. Can the new government revive it? Caroline Lambert reports

Published
2009
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