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1. Moving beyond the T cell synapse for combination neoadjuvant immunotherapy in head and neck cancer

Author

R. Bryan Bell, Michael Gough, Marka Crittenden, and Kristina Young

Subjects
Medicine
Abstract

Patients with HPV-unrelated head and neck squamous cell carcinoma (HPV-unrelated HNSCC) show only modest benefit from treatment with PD-1 inhibitors (PD-1i). Targeting transforming growth factor β (TGF-β) may make PD-1i more effective by inducing T cell responses. In this issue of the JCI, Redman et al. performed a clinical trial in 14 patients with HPV-unrelated HNSCC using bintrafusp alfa, a bifunctional fusion protein that blocks PD-L1 and TGF-β. Primary tumors displayed pathologic responses with 5 of 14 patients having at least a partial response. While no primary tumor or metastatic lymph node demonstrated a complete pathologic response, the findings suggest that concurrent neoadjuvant inhibition of PD-L1 and TGF-β may provide a rational strategy to improve pathologic response and clinical outcome in patients with HPV-unrelated HNSCC.

Published
2022
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2. Explant Modeling of the Immune Environment of Head and Neck Cancer

Author

Shay Sharon, Thomas Duhen, Shelly Bambina, Jason Baird, Rom Leidner, Bryan Bell, Nardy Casap, Marka Crittenden, Swetha Vasudevan, Maria Jubran, Nataly Kravchenko-Balasha, and Michael Gough

Subjects
tumor, head and neck cancer, immunotherapy, explant, cytokine, PD1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Patients exhibit distinct responses to immunotherapies that are thought to be linked to their tumor immune environment. However, wide variations in outcomes are also observed in patients with matched baseline tumor environments, indicating that the biological response to treatment is not currently predictable using a snapshot analysis. To investigate the relationship between the immune environment of tumors and the biological response to immunotherapies, we characterized four murine head and neck squamous cell carcinoma (HNSCC) models on two genetic backgrounds. Using tumor explants from those models, we identified correlations between the composition of infiltrating immune cells and baseline cytokine profiles prior to treatment. Following treatment with PD-1 blockade, CTLA-4 blockade, or OX40 stimulation, we observed inter-individual variability in the response to therapy between genetically identical animals bearing the same tumor. These distinct biological responses to treatment were not linked to the initial tumor immune environment, meaning that outcome would not be predictable from a baseline analysis of the tumor infiltrates. We similarly performed the explant assay on patient HNSCC tumors and found significant variability between the baseline environment of the tumors and their response to therapy. We propose that tumor explants provide a rapid biological assay to assess response to candidate immunotherapies that may allow matching therapies to individual patient tumors. Further development of explant approaches may allow screening and monitoring of treatment responses in HNSCC.

Published
2021
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3. Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma

Author

Allen C Cheng, Hong Xiao, Marka Crittenden, Carlo Bifulco, Michael Gough, Kristina Young, Walter J Urba, R Bryan Bell, Yaping Wu, George Morris, Marcus A Couey, Ashish A Patel, Amber L Watters, Lessli Rushforth, and Shorin Nemeth

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck squamous cell carcinoma (HNSCC); however, response rates are modest. We hypothesized that adding stereotactic body radiation therapy (SBRT) to anti-PD-1 would be safe prior to definitive surgical resection and would enhance pathological response compared with historical cohorts of patients with locoregionally advanced HNSCC treated with checkpoint inhibitor alone.Methods The Neoadjuvant Immuno-Radiotherapy Trial was an investigator-initiated single institution phase Ib clinical trial that enrolled patients with previously untreated locally advanced HPV-positive and HPV-negative HNSCC between 2018 and 2019. Eligible patients were treated with neoadjuvant SBRT at a total dose of either 40 Gy in 5 fractions or 24 Gy in 3 fractions, delivered in a 1-week timespan, with or without nivolumab, prior to definitive surgical resection. Patients were then planned for treatment with adjuvant nivolumab for 3 months. The primary safety endpoint was unplanned delay in surgery considered to be at least possibly related to neoadjuvant treatment. The primary efficacy endpoints included pathological complete response (pCR), major pathological response (mPR), and the rate of clinical to pathological downstaging after neoadjuvant treatment.Results Twenty-one patients underwent neoadjuvant treatment, which was well tolerated and did not delay surgery, thus meeting the primary endpoint. Tissue responses were characterized by robust inflammatory infiltrates in the regression bed, plasma cells and cholesterol clefts. Among the entire study group, the mPR and pCR rate was 86% and 67%, respectively. Clinical to pathological downstaging occurred in 90% of the patients treated.Conclusion These data demonstrate that radiation delivered only to the gross tumor volume combined with immunotherapy was safe, resulted in a high rate of mPR and should be further evaluated as a locally focused neoadjuvant therapy for patients with head and neck cancer.Trial registration number This study is registered with clinicaltrials.gov (NCT03247712) and is active, but closed to patient accrual.

Published
2021
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4. Germinal center reactions in tertiary lymphoid structures associate with neoantigen burden, humoral immunity and long-term survivorship in pancreatic cancer

Author

Andrew J. Gunderson, Venkatesh Rajamanickam, Cynthia Bui, Brady Bernard, Joanna Pucilowska, Carmen Ballesteros-Merino, Mark Schmidt, Kayla McCarty, Michaela Philips, Brian Piening, Christopher Dubay, Terry Medler, Phillipa Newell, Paul Hansen, Eric Tran, Ephraim Tang, Carlo Bifulco, Marka Crittenden, Michael Gough, and Kristina H. Young

Subjects
tls, b cells, pancreatic cancer, immunotherapy, t cells, neoantigens, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has traditionally been thought of as an immunologically quiescent tumor type presumably because of a relatively low tumor mutational burden (TMB) and poor responses to checkpoint blockade therapy. However, many PDAC tumors exhibit T cell inflamed phenotypes. The presence of tertiary lymphoid structures (TLS) has recently been shown to be predictive of checkpoint blockade response in melanomas and sarcomas, and are prognostic for survival in PDAC. In order to more comprehensively understand tumor immunity in PDAC patients with TLS, we performed RNA-seq, single and multiplex IHC, flow cytometry and predictive genomic analysis on treatment naïve, PDAC surgical specimens. Forty-six percent of tumors contained distinct T and B cell aggregates reflective of “early-stage TLS” (ES-TLS), which correlated with longer overall and progression-free survival. These tumors had greater CD8+ T cell infiltration but were not defined by previously published TLS gene-expression signatures. ES-TLS+ tumors were enriched for IgG1 class-switched memory B cells and memory CD4+ T cells, suggesting durable immunological memory persisted in these patients. We also observed the presence of active germinal centers (mature-TLS) in 31% of tumors with lymphocyte clusters, whose patients had long-term survival (median 56 months). M-TLS-positive tumors had equivalent overall T cell infiltration to ES-TLS, but were enriched for activated CD4+ memory cells, naive B cells and NK cells. Finally, using a TCGA-PDAC dataset, ES-TLS+ tumors harbored a decreased TMB, but M-TLS with germinal centers expressed significantly more MHCI-restricted neoantigens as determined by an in silico neoantigen prediction method. Interestingly, M-TLS+ tumors also had evidence of increased rates of B cell somatic hypermutation, suggesting that germinal centers form in the presence of high-quality tumor neoantigens leading to increased humoral immunity that confers improved survival for PDAC patients. AbbreviationsTLS: tertiary lymphoid structures; GC: germinal center(s); PDAC: pancreatic ductal adenocarcinoma; RNA-seq: RNA sequencing; BCRseq: B cell receptor sequencing; HEV: high endothelial venule; PNAd: peripheral node addressin; TMB: tumor mutational burden; TCGA: the cancer genome atlas; PAAD: pancreatic adenocarcinoma; FFPE: formalin fixed paraffin embedded; TIME: tumor immune microenvironment.

Published
2021
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5. Characterization of a Novel Compound That Stimulates STING-Mediated Innate Immune Activity in an Allele-Specific Manner

Author

Jinu Abraham, Sara Botto, Nobuyo Mizuno, Kara Pryke, Bryan Gall, Dylan Boehm, Tina M. Sali, Haihong Jin, Aaron Nilsen, Michael Gough, Jason Baird, Marita Chakhtoura, Caroline Subra, Lydie Trautmann, Elias K. Haddad, and Victor R. DeFilippis

Subjects
interferon, cytokine, cytosolic DNA sensing, STING, adjuvant, Immunologic diseases. Allergy, RC581-607
Abstract

The innate immune response to cytosolic DNA involves transcriptional activation of type I interferons (IFN-I) and proinflammatory cytokines. This represents the culmination of intracellular signaling pathways that are initiated by pattern recognition receptors that engage DNA and require the adaptor protein Stimulator of Interferon Genes (STING). These responses lead to the generation of cellular and tissue states that impair microbial replication and facilitate the establishment of long-lived, antigen-specific adaptive immunity. Ultimately this can lead to immune-mediated protection from infection but also to the cytotoxic T cell-mediated clearance of tumor cells. Intriguingly, pharmacologic activation of STING-dependent phenotypes is known to enhance both vaccine-associated immunogenicity and immune-based anti-tumor therapies. Unfortunately, the STING protein exists as multiple variant forms in the human population that exhibit differences in their reactivity to chemical stimuli and in the intensity of molecular signaling they induce. In light of this, STING-targeting drug discovery efforts require an accounting of protein variant-specific activity. Herein we describe a small molecule termed M04 that behaves as a novel agonist of human STING. Importantly, we find that the molecule exhibits a differential ability to activate STING based on the allelic variant examined. Furthermore, while M04 is inactive in mice, expression of human STING in mouse cells rescues reactivity to the compound. Using primary human cells in ex vivo assays we were also able to show that M04 is capable of simulating innate responses important for adaptive immune activation such as cytokine secretion, dendritic cell maturation, and T cell cross-priming. Collectively, this work demonstrates the conceivable utility of a novel agonist of human STING both as a research tool for exploring STING biology and as an immune potentiating molecule.

Published
2020
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6. A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses

Author

Kara M. Pryke, Jinu Abraham, Tina M. Sali, Bryan J. Gall, Iris Archer, Andrew Liu, Shelly Bambina, Jason Baird, Michael Gough, Marita Chakhtoura, Elias K. Haddad, Ilsa T. Kirby, Aaron Nilsen, Daniel N. Streblow, Alec J. Hirsch, Jessica L. Smith, and Victor R. DeFilippis

Subjects
antiviral agents, emerging virus, innate immunity, interferons, Microbiology, QR1-502
Abstract

ABSTRACT The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy’s potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl)-2-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione, which we termed AV-C. Treatment of human cells with AV-C activates innate and interferon-associated responses that strongly inhibit replication of Zika, Chikungunya, and dengue viruses. By utilizing genome editing, we investigated the host proteins essential to AV-C-induced cellular states. This showed that the compound requires a TRIF-dependent signaling cascade that culminates in IFN regulatory factor 3 (IRF3)-dependent expression and secretion of type I interferon to elicit antiviral responses. The other canonical IRF3-terminal adaptor proteins STING and IPS-1/MAVS were dispensable for AV-C-induced phenotypes. However, our work revealed an important inhibitory role for IPS-1/MAVS, but not TRIF, in flavivirus replication, implying that TRIF-directed viral evasion may not occur. Additionally, we show that in response to AV-C, primary human peripheral blood mononuclear cells secrete proinflammatory cytokines that are linked with establishment of adaptive immunity to viral pathogens. Ultimately, synthetic innate immune activators such as AV-C may serve multiple therapeutic purposes, including direct antimicrobial responses and facilitation of pathogen-directed adaptive immunity. IMPORTANCE The type I interferon system is part of the innate immune response that has evolved in vertebrates as a first line of broad-spectrum immunological defense against an unknowable diversity of microbial, especially viral, pathogens. Here, we characterize a novel small molecule that artificially activates this response and in so doing generates a cellular state antagonistic to growth of currently emerging viruses: Zika virus, Chikungunya virus, and dengue virus. We also show that this molecule is capable of eliciting cellular responses that are predictive of establishment of adaptive immunity. As such, this agent may represent a powerful and multipronged therapeutic tool to combat emerging and other viral diseases.

Published
2017
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7. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic

Author

Maximilian Richter, Roma Yumul, Kamola Saydaminova, Hongjie Wang, Michael Gough, Audrey Baldessari, Roberto Cattaneo, Frank Lee, Chung-Huei Katherine Wang, Haishan Jang, Anne Astier, Ajay Gopal, Darrick Carter, and André Lieber

Subjects
Genetics, QH426-470, Cytology, QH573-671
Abstract

Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs). The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs) with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with rituximab in the treatment of patients with B-cell malignancies.

Published
2016
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8. Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the Comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial

Author

Julie Brittenden, Seonaidh C Cotton, Andrew Elders, Emma Tassie, Graham Scotland, Craig R Ramsay, John Norrie, Jennifer Burr, Jill Francis, Samantha Wileman, Bruce Campbell, Paul Bachoo, Ian Chetter, Michael Gough, Jonothan Earnshaw, Tim Lees, Julian Scott, Sara A Baker, Graeme MacLennan, Maria Prior, Denise Bolsover, and Marion K Campbell

Subjects
randomised controlled trial, varicose veins, endovenous laser ablation, foam sclerotherapy, surgery, class, bravvo, Medical technology, R855-855.5
Abstract

Background: Foam sclerotherapy (foam) and endovenous laser ablation (EVLA) have emerged as alternative treatments to surgery for patients with varicose veins, but uncertainty exists regarding their effectiveness in the medium to longer term. Objectives: To assess the clinical effectiveness and cost-effectiveness of foam, EVLA and surgery for the treatment of varicose veins. Design: A parallel-group randomised controlled trial (RCT) without blinding, and economic modelling evaluation. Setting: Eleven UK specialist vascular centres. Participants: Seven hundred and ninety-eight patients with primary varicose veins (foam, n = 292; surgery, n = 294; EVLA, n = 212). Interventions: Patients were randomised between all three treatment options (eight centres) or between foam and surgery (three centres). Primary outcome measures: Disease-specific [Aberdeen Varicose Vein Questionnaire (AVVQ)] and generic [European Quality of Life-5 Dimensions (EQ-5D), Short Form questionnaire-36 items (SF-36) physical and mental component scores] quality of life (QoL) at 6 months. Cost-effectiveness as cost per quality-adjusted life-year (QALY) gained. Secondary outcome measures: Quality of life at 6 weeks; residual varicose veins; Venous Clinical Severity Score (VCSS); complication rates; return to normal activity; truncal vein ablation rates; and costs. Results: The results appear generalisable in that participants’ baseline characteristics (apart from a lower-than-expected proportion of females) and post-treatment improvement in outcomes were comparable with those in other RCTs. The health gain achieved in the AVVQ with foam was significantly lower than with surgery at 6 months [effect size −1.74, 95% confidence interval (CI) −2.97 to −0.50; p = 0.006], but was similar to that achieved with EVLA. The health gain in SF-36 mental component score for foam was worse than that for EVLA (effect size 1.54, 95% CI 0.01 to 3.06; p = 0.048) but similar to that for surgery. There were no differences in EQ-5D or SF-36 component scores in the surgery versus foam or surgery versus EVLA comparisons at 6 months.: The trial-based cost-effectiveness analysis showed that, at 6 months, foam had the highest probability of being considered cost-effective at a ceiling willingness-to-pay ratio of £20,000 per QALY. EVLA was found to cost £26,107 per QALY gained versus foam, and was less costly and generated slightly more QALYs than surgery. Markov modelling using trial costs and the limited recurrence data available suggested that, at 5 years, EVLA had the highest probability (≈ 79%) of being cost-effective at conventional thresholds, followed by foam (≈ 17%) and surgery (≈ 5%).: With regard to secondary outcomes, health gains at 6 weeks (p

Published
2015
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9. Preclinical safety and efficacy studies with an affinity-enhanced epithelial junction opener and PEGylated liposomal doxorubicin

Author

Maximilian Richter, Roma Yumul, Hongjie Wang, Kamola Saydaminova, Martin Ho, Drew May, Audrey Baldessari, Michael Gough, Charles Drescher, Nicole Urban, Steve Roffler, Chloé Zubieta, Darrick Carter, Pascal Fender, and André Lieber

Subjects
Genetics, QH426-470, Cytology, QH573-671
Abstract

A central treatment resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. We have developed a small recombinant protein (JO-1) that triggers the transient opening of intercellular junctions and thus increases the efficacy of monoclonal antibodies and chemotherapeutic drugs without causing toxicity in mouse tumor models. Here, we provide data toward the clinical translation of an affinity-enhanced version of JO-1, which we call JO-4, in combination with PEGylated liposomal doxorubicin (PLD)/Doxil for ovarian cancer therapy. We have presented X-ray crystallography data suggesting a structural basis for the higher affinity of JO-4 to DSG2. We also confirmed JO-4 efficacy in a xenograft model with primary ovarian cancer cells showing that JO-4 can salvage Doxil therapy when given at a dose that was threefold lower than the therapeutic dose. Furthermore, we tested the safety of intravenous JO-4 alone and in combination with Doxil in Macaca fascicularis, an adequate animal model for predicting toxicity in humans. Our studies did not show critical JO-4-related toxicity or an increase of Doxil-related side effects. Our efficacy and safety data will help to support an Investigational new drug-filing for a JO-4/Doxil combination treatment.

Published
2015
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10. Optimising the hatching success of artificially incubated eggs for use in a conservation program for the western saw-shelled turtle (

Author

Louise M. Streeting, Deborah S. Bower, Martin L. Dillon, Phil Spark, Michael Gough, Adam Skidmore, Paul G. McDonald, Hannah Delaney, Adrienne Burns, Sandy Watson, Duminda S. B. Dissanayake, Arthur Georges, and Donald T. McKnight

Subjects
Animal Science and Zoology, Ecology, Evolution, Behavior and Systematics
Abstract

Artificial incubation of eggs and the release of hatchlings into the wild is a common conservation intervention designed to augment threatened turtle populations. We investigate a range of incubation temperatures to establish an optimal temperature for maximum hatching success of western saw-shelled turtle (Myuchelys bellii) eggs. We report on the influence of incubation temperature on incubation duration and hatching success and describe two experimental incubation methods which, for the same incubation temperature (27°C), resulted in 77% and 97% hatching success, respectively. Eggs were incubated at constant temperatures (27°C, 28°C and 29°C) to determine the influence of temperature on incubation period, hatchling morphology and external residual yolk. Incubation duration was negatively correlated with incubation temperature. We report on the morphology of eggs and hatchlings and show that their dimensions are positively correlated with maternal adult size and mass. A constant incubation temperature of 27°C produced the highest hatching success and smallest external residual yolk on hatching and is therefore recommended for incubation of eggs for population reinforcement programs. Our study is the first to optimise artificial incubation procedures for M. bellii and will be a valuable resource for M. bellii and other threatened freshwater turtle conservation initiatives.

Published
2022

11. The Stanford Hall consensus statement for post-COVID-19 rehabilitation

Author

Philippa Turner, Mark Cranley, Alexander N. Bennett, Robert M. Barker-Davies, Rhodri Phillip, Alastair M. Nicol, Polly Baker, Daniel Sherwood, Theodora Papadopoulou, David Roscoe, Sardar Bahadur, Duncan Goodall, Oliver O'Sullivan, Kahawalage Pumi Prathima Senaratne, Michael Gough, Henrietta Ellis, Jonathan Norman, Alan Mistlin, Shreshth Dharm-Datta, Tammy Walker, and Sarah Lewis

Subjects
medicine.medical_specialty, Sports medicine, medicine.medical_treatment, Pneumonia, Viral, Physical Therapy, Sports Therapy and Rehabilitation, virus, recovery, Betacoronavirus, 03 medical and health sciences, 0302 clinical medicine, Quality of life (healthcare), Humans, Medicine, Orthopedics and Sports Medicine, 030212 general & internal medicine, Grading (education), Pandemics, Neurorehabilitation, Rehabilitation, biology, SARS-CoV-2, business.industry, Athletes, Consensus Statement, COVID-19, General Medicine, Evidence-based medicine, biology.organism_classification, United Kingdom, Military personnel, consensus, Family medicine, Coronavirus Infections, business, sports and exercise medicine, 030217 neurology & neurosurgery
Abstract

The highly infectious and pathogenic novel coronavirus (CoV), severe acute respiratory syndrome (SARS)-CoV-2, has emerged causing a global pandemic. Although COVID-19 predominantly affects the respiratory system, evidence indicates a multisystem disease which is frequently severe and often results in death. Long-term sequelae of COVID-19 are unknown, but evidence from previous CoV outbreaks demonstrates impaired pulmonary and physical function, reduced quality of life and emotional distress. Many COVID-19 survivors who require critical care may develop psychological, physical and cognitive impairments. There is a clear need for guidance on the rehabilitation of COVID-19 survivors. This consensus statement was developed by an expert panel in the fields of rehabilitation, sport and exercise medicine (SEM), rheumatology, psychiatry, general practice, psychology and specialist pain, working at the Defence Medical Rehabilitation Centre, Stanford Hall, UK. Seven teams appraised evidence for the following domains relating to COVID-19 rehabilitation requirements: pulmonary, cardiac, SEM, psychological, musculoskeletal, neurorehabilitation and general medical. A chair combined recommendations generated within teams. A writing committee prepared the consensus statement in accordance with the appraisal of guidelines research and evaluation criteria, grading all recommendations with levels of evidence. Authors scored their level of agreement with each recommendation on a scale of 0–10. Substantial agreement (range 7.5–10) was reached for 36 recommendations following a chaired agreement meeting that was attended by all authors. This consensus statement provides an overarching framework assimilating evidence and likely requirements of multidisciplinary rehabilitation post COVID-19 illness, for a target population of active individuals, including military personnel and athletes.

Published
2020

13. Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Author

Alison Halliday, Richard Bulbulia, Leo H Bonati, Johanna Chester, Andrea Cradduck-Bamford, Richard Peto, Hongchao Pan, John Potter, Hans Henning Eckstein, Barbara Farrell, Marcus Flather, Averil Mansfield, Boby Mihaylova, Kazim Rahimi, David Simpson, Dafydd Thomas, Peter Sandercock, Richard Gray, Andrew Molyneux, Cliff P Shearman, Peter Rothwell, Anna Belli, Will Herrington, Parminder Judge, Peter Leopold, Marion Mafham, Michael Gough, Piergiorgio Cao, Sumaira MacDonald, Vasha Bari, Clive Berry, S Bradshaw, Wojciech Brudlo, Alison Clarke, Robin Cox, Susan Fathers, Kamran Gaba, Mo Gray, Elizabeth Hayter, Constance Holliday, Rijo Kurien, Michael Lay, Steffi le Conte, Jessica McManus, Zahra Madgwick, Dylan Morris, Andrew Munday, Sandra Pickworth, Wiktor Ostasz, Michiel Poorthuis, Sue Richards, Louisa Teixeira, Sergey Tochlin, Lynda Tully, Carol Wallis, Monique Willet, Alan Young, Renato Casana, Chiara Malloggi, Andrea Odero Jr, Vincenzo Silani, Gianfranco Parati, Giuseppe Malchiodi, Giovanni Malferrari, Francesco Strozzi, Nicola Tusini, Enrico Vecchiati, Gioacchino Coppi, Antonio Lauricella, Roberto Moratto, Roberto Silingardi, Jessica Veronesi, Andrea Zini, Emanuele Ferrero, Michelangelo Ferri, Andrea Gaggiano, Carmelo Labate, Franco Nessi, Daniele Psacharopulo, Andrea Viazzo, Giovanni Malacrida, Daniela Mazzaccaro, Giovanni Meola, Alfredo Modafferi, Giovanni Nano, Maria Teresa Occhiuto, Paolo Righini, Silvia Stegher, Stefano Chiarandini, Filippo Griselli, Sandro Lepidi, Fabio Pozzi Mucelli, Marcello Naccarato, Mario D'Oria, Barbara Ziani, Andrea Stella, Mortalla Dieng, Gianluca Faggioli, Mauro Gargiulo, Sergio Palermo, Rodolfo Pini, Giovanni Maria Puddu, Andrea Vacirca, Domenico Angiletta, Claudio Desantis, Davide Marinazzo, Giovanni Mastrangelo, Guido Regina, Raffaele Pulli, Paolo Bianchi, Lea Cireni, Elisabetta Coppi, Rocco Pizzirusso, Filippo Scalise, Giovanni Sorropago, Valerio Tolva, Valeria Caso, Enrico Cieri, Paola DeRango, Luca Farchioni, Giacomo Isernia, Massimo Lenti, Gian Battista Parlani, Guglielmo Pupo, Grazia Pula, Gioele Simonte, Fabio Verzini, Federico Carimati, Maria Luisa Delodovici, Federico Fontana, Gabriele Piffaretti, Matteo Tozzi, Efrem Civilini, Giorgio Poletto, Bernhard Reimers, Barbara Praquin, Sonia Ronchey, Laura Capoccia, Wassim Mansour, Enrico Sbarigia, Francesco Speziale, Pasqualino Sirignano, Danilo Toni, Roberto Galeotti, Vincenzo Gasbarro, Francesco Mascoli, Tiberio Rocca, Elpiniki Tsolaki, Giulia Bernardini, Ester DeMarco, Alessia Giaquinta, Francesco Patti, Massimiliano Veroux, Pierfrancesco Veroux, Carla Virgilio, Nicola Mangialardi, Matteo Orrico, Vincenzo Di Lazzaro, Nunzio Montelione, Francesco Spinelli, Francesco Stilo, Carlo Cernetti, Sandro Irsara, Giuseppe Maccarrone, Diego Tonello, Adriana Visonà, Beniamino Zalunardo, Emiliano Chisci, Stefano Michelagnoli, Nicola Troisi, Maela Masato, Massimo Dei Negri, Andrea Pacchioni, Salvatore Saccà, Giovanni Amatucci, Alfredo Cannizzaro, Federico Accrocca, Cesare Ambrogi, Renzo Barbazza, Giustino Marcucci, Andrea Siani, Guido Bajardi, Giovanni Savettieri, Angelo Argentieri, Riccardo Corbetta, Attilio Odero, Pietro Quaretti, Federico Z Thyrion, Alessandro Cappelli, Domenico Benevento, Gianmarco De Donato, Maria Agnese Mele, Giancarlo Palasciano, Daniela Pieragalli, Alessandro Rossi, Carlo Setacci, Francesco Setacci, Domenico Palombo, Maria Cecilia Perfumo, Edoardo Martelli, Aldo Paolucci, Santi Trimarchi, Viviana Grassi, Luigi Grimaldi, Giuliana La Rosa, Domenico Mirabella, Matteo Scialabba, Leonildo Sichel, Costantino L D'Angelo, Gian Franco Fadda, Holta Kasemi, Mario Marino, Francesco Burzotta, Francesco Alberto Codispoti, Angela Ferrante, Giovanni Tinelli, Yamume Tshomba, Claudio Vincenzoni, Deborah Amis, Dawn Anderson, Martin Catterson, Mike Clarke, Michelle Davis, Anand Dixit, Alexander Dyker, Gary Ford, Ralph Jackson, Sreevalsan Kappadath, David Lambert, Tim Lees, Stephen Louw, James McCaslin, Noala Parr, Rebecca Robson, Gerard Stansby, Lucy Wales, Vera Wealleans, Lesley Wilson, Michael Wyatt, Hardeep Baht, Ibrahim Balogun, Ilse Burger, Tracy Cosier, Linda Cowie, Gunaratnam Gunathilagan, David Hargroves, Robert Insall, Sally Jones, Hannah Rudenko, Natasha Schumacher, Jawaharlal Senaratne, George Thomas, Audrey Thomson, Tom Webb, Ellen Brown, Bernard Esisi, Ali Mehrzad, Shane MacSweeney, Norman McConachie, Alison Southam, Wayne Sunman, Ahmed Abdul-Hamiq, Jenny Bryce, Ian Chetter, Duncan Ettles, Raghuram Lakshminarayan, Kim Mitchelson, Christopher Rhymes, Graham Robinson, Paul Scott, Alison Vickers, Ray Ashleigh, Stephen Butterfield, Ed Gamble, Jonathan Ghosh, Charles N McCollum, Mark Welch, Sarah Welsh, Leszek Wolowczyk, Mary Donnelly, Stephen D'Souza, Anselm A Egun, Bindu Gregary, Thomas Joseph, Christine Kelly, Shuja Punekar, M Asad Rahi, Sonia Raj, Dare Seriki, George Thomson, James Brown, Ragunath Durairajan, Iris Grunwald, Paul Guyler, Paula Harman, Matthew Jakeways, Christopher Khuoge, Ashish Kundu, Thayalini Loganathan, Nisha Menon, Raji O Prabakaran, Devesh Sinha, Vicky Thompson, Sharon Tysoe, Dennis Briley, Chris Darby, Linda Hands, Dominic Howard, Wilhelm Kuker, Ursula Schulz, Rachel Teal, David Barer, Andrew Brown, Susan Crawford, Paul Dunlop, Ramesh Krishnamurthy, Nikhil Majmudar, Duncan Mitchell, Min P Myint, Richard O'Brien, Janice O'Connell, Naweed Sattar, Shanmugam Vetrivel, Jonathan Beard, Trevor Cleveland, Peter Gaines, John Humphreys, Alison Jenkins, Craig King, Daniel Kusuma, Ralph Lindert, Robbie Lonsdale, Raj Nair, Shah Nawaz, Faith Okhuoya, Douglas Turner, Graham Venables, Paul Dorman, Andrea Hughes, Deborah Jones, David Mendelow, Helen Rodgers, Aidas Raudoniitis, Peter Enevoldson, Hans Nahser, Imelda O'Brien, Francesco Torella, Dave Watling, Richard White, Pauline Brown, Dipankar Dutta, Lorraine Emerson, Paula Hilltout, Sachin Kulkarni, Jackie Morrison, Keith Poskitt, Fiona Slim, Sarah Smith, Amanda Tyler, Joanne Waldron, Mark Whyman, Milda Bajoriene, Lucy 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Noordhout A., Malmendier D., Massoz M., Saad G., Bosiers M., Callaert J., Deloose K., Blanco Canibano E., Garcia Fresnillo B., Guerra Requena M., Morata Barrado P.C., Muela Mendez M., Yusta Izquierdo A., Aparici Robles F., Blanes Orti P., Garcia Dominguez L., Martinez Lopez R., Miralles Hernandez M., Tembl Ferrairo J.I., Chamorro A., Macho J., Obach V., Riambau V., San Roman L., Ahlhelm F.J., Blackham K., Engelter S., Eugster T., Gensicke H., Gurke L., Lyrer P., Mariani L., Maurer M., Mujagic E., Muller M., Psychogios M., Stierli P., Stippich C., Traenka C., Wolff T., Wagner B., Wiegert M.M., Clarke S., Diepers M., Grochenig E., Gruber P., Isaak A., Kahles T., Marti R., Nedeltchev K., Remonda L., Tissira N., Valenca Falcao M., de Borst G.J., Lo R.H., Moll F.L., Toorop R., van der Worp B.H., Vonken E.J., Kappelle J.L., Jahrome O., Vos F., Schuiling W., van Overhagen H., Keunen R.W.M., Knippenberg B., Wever J.J., Lardenoije J.W., Reijnen M., Smeets L., van Sterkenburg S., Fraedrich G., Gizewski E., Gruber I., Knoflach M., Kiechl S., Rantner B., Abdulamit T., Bergeron P., Padovani R., Trastour J.-C., Cardon J.-M., Le Gallou-Wittenberg A., Allaire E., Becquemin J.-P., Cochennec-Paliwoda F., Desgranges P., Hosseini H., Kobeiter H., Marzelle J., Almekhlafi M.A., Bal S., Barber P.A., Coutts S.B., Demchuk A.M., Eesa M., Gillies M., Goyal M., Hill M.D., Hudon M.E., Jambula A., Kenney C., Klein G., McClelland M., Mitha A., Menon B.K., Morrish W.F., Peters S., Ryckborst K.J., Samis G., Save S., Smith E.E., Stys P., Subramaniam S., Sutherland G.R., Watson T., Wong J.H., Zimmel L., Flis V., Matela J., Miksic K., Milotic F., Mrdja B., Stirn B., Tetickovic E., Gasparini M., Grad A., Kompara I., Milosevic Z., Palmiste V., Toomsoo T., Aidashova B., Kospanov N., Lyssenko R., Mussagaliev D., Beyar R., Hoffman A., Karram T., Kerner A., Nikolsky E., Nitecki S., Andonova S., Bachvarov C., Petrov V., Cvjetko I., Vidjak V., Haluzan D., Petrunic M., Liu B., Liu C.-W., Bartko D., Beno P., Rusnak F., Zelenak K., Ezura M., Inoue T., Kimura N., Kondo R., Matsumoto Y., Shimizu H., Endo H., Furui E., Bakke S., Krohg-Sorensen K., Nome T., Skjelland M., Tennoe B., Albuquerque e Castro J., Alves G., Bastos Goncalves F., de Aragao Morais J., Garcia A.C., Valentim H., Vasconcelos L., Belcastro F., Cura F., Zaefferer P., Abd-Allah F., Eldessoki M.H., Heshmat Kassem H., Soliman Gharieb H., Colgan M.P., Haider S.N., Harbison J., Madhavan P., Moore D., Shanik G., Kazan V., Nazzal M., Ramsey-Williams V., and Gargiulo M

Subjects
Male, medicine.medical_specialty, Time Factors, Time Factor, medicine.medical_treatment, Carotid Stenosi, MEDLINE, Carotid endarterectomy, Rate ratio, Risk Assessment, Asymptomatic, law.invention, Randomized controlled trial, law, Risk Factors, carotid artery stenting (CAS), carotid endarterectomy (CEA), Stent, medicine, Humans, Carotid Stenosis, Stroke, Endarterectomy, Aged, Endarterectomy, Carotid, business.industry, carotid artery, Risk Factor, Articles, General Medicine, trial, medicine.disease, Settore MED/22 - CHIRURGIA VASCOLARE, Surgery, Stenosis, Treatment Outcome, Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Female, Stents, Human medicine, medicine.symptom, business, Human
Abstract

Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.

Published
2021

14. Five-Year Outcomes of a Randomized Trial of Treatments for Varicose Veins

Author

Graeme MacLennan, Marion K Campbell, David A. Cooper, Julian Scott, Andrew Elders, Ian Chetter, Paul Bachoo, Julie Brittenden, Bruce Campbell, Craig R Ramsay, Jill J Francis, Sara A Baker, Seonaidh Cotton, Jonothan Earnshaw, John Norrie, Jennifer Burr, Michael Gough, Maria Dimitrova, Emma Tassie, Tim Lees, Graham Scotland, University of St Andrews. Population and Behavioural Science Division, and University of St Andrews. School of Medicine

Subjects
Adult, Male, RM, medicine.medical_specialty, Cost effectiveness, Cost-Benefit Analysis, medicine.medical_treatment, 030204 cardiovascular system & hematology, law.invention, Varicose Veins, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Surveys and Questionnaires, Sclerotherapy, Varicose veins, Humans, Medicine, 030212 general & internal medicine, R2C, Ultrasonography, Interventional, Intention-to-treat analysis, business.industry, ~DC~, Endovascular Procedures, Great saphenous vein, RD Surgery, 3rd-DAS, General Medicine, Middle Aged, RM Therapeutics. Pharmacology, Intention to Treat Analysis, Quality-adjusted life year, Surgery, Clinical trial, Treatment Outcome, Quality of Life, Female, Laser Therapy, Quality-Adjusted Life Years, medicine.symptom, BDC, business, RD, Follow-Up Studies
Abstract

Funded by the Health Technology Assessment Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN51995477. Background : Endovenous laser ablation and ultrasound-guided foam sclerotherapy are recommended alternatives to surgery for the treatment of primary varicose veins, but their long-term comparative effectiveness remains uncertain. Methods : In a randomized, controlled trial involving 798 participants with primary varicose veins at 11 centers in the United Kingdom, we compared the outcomes of laser ablation, foam sclerotherapy, and surgery. Primary outcomes at 5 years were disease-specific quality of life and generic quality of life, as well as cost-effectiveness based on models of expected costs and quality-adjusted life-years (QALYs) gained that used data on participants’ treatment costs and scores on the EuroQol EQ-5D questionnaire. Results : Quality-of-life questionnaires were completed by 595 (75%) of the 798 trial participants. After adjustment for baseline scores and other covariates, scores on the Aberdeen Varicose Vein Questionnaire (on which scores range from 0 to 100, with lower scores indicating a better quality of life) were lower among patients who underwent laser ablation or surgery than among those who underwent foam sclerotherapy (effect size [adjusted differences between groups] for laser ablation vs. foam sclerotherapy, −2.86; 95% confidence interval [CI], −4.49 to −1.22; P

Published
2019

16. A phase II trial of TGFβ type I receptor inhibitor, galunisertib, plus neoadjuvant chemoradiation in patients with locally advanced rectal cancer

Author

Kristina Hoot Young, Andrew J Gunderson, Miranda Gilchrist, Mark Whiteford, Maria X Kiely, Amanda Hayman, David P O'Brien, Rehan Ahmad, Jeffrey V Manchio, Evelyn Brosnan, Gina M. Vaccaro, Rui Li, Miklos Simon, Mary McCormick, Ashley Drokin, Julie Cramer, Walter John Urba, Michael Gough, Marka R. Crittenden, and Tomoko Yamazaki

Subjects
Cancer Research, Oncology
Abstract

3617 Background: Transforming growth factor beta (TGFβ) is an immunosuppressive cytokine upregulated in colorectal cancer. Preclinical data demonstrated improved response to chemoradiation with TGFβ blockade in colorectal adenocarcinoma. Here we report the results of our single arm Phase II study combining the TGFβ type I receptor kinase inhibitor, galunisertib, with neoadjuvant chemoradiation in patients with locally advanced rectal adenocarcinoma. Methods: Eligible patients had T3+ or N+ rectal adenocarcinoma planned for surgical resection. Enrolled patients completed a 14-day course of galunisertib, followed by chemoradiation with continuous infusion 5-fluorouracil or capecitabine with radiation to 50.4-54Gy in 28-30 fractions. On day 30, patients underwent another 14-day course of galunisertib concurrent with ongoing chemoradiation. Five to nine weeks after completing neoadjuvant therapy, patients underwent response assessment. Those with complete response by physical exam, proctoscopy, and MRI, could opt for non-operative management and proceed to mFOLFOX6. Those with less than a complete response underwent surgical resection. The primary endpoint was complete response rate (CR), which was a composite of pathologic complete responses in those patients who proceeded to surgery, and clinical complete responses maintained at 1 year after completion of therapy for those who chose non-operative management. Using a Simon Two-Stage approach with 90% power and α = 0.05, to detect a 20% improvement in complete response rate compared to historical control (15% vs 35%); we reject the null hypothesis if ≥10/38 patients have a CR. 38 patients were enrolled with 35 patients evaluable. Results: Median age was 51y, 68% of patients were male, 87% of patients were Stage III, 97% of patients were node-positive, and 97% were proficient in mismatch repair. 95% of patients completed study therapy. Toxicity attributed to galunisertib was Grade 1-2. 28 patients went to surgery, with a mean neoadjuvant rectal (NAR) score (NAR = 5pN-3(cT-pT)+12]2/9.61) of 11.29, and pCR in 7 patients. 7 patients underwent non-operative management, with 5 achieving cCR at 1 year. Therefore, complete responses were observed in 12 patients. Peripheral immune monitoring revealed percent change in CD3+CD4-CXCR3+ T cells and activated CD8EM T cells correlated with response to therapy. 2y PFS and OS were 81.5% and 97%. Conclusions: The addition of TGFβ inhibition to neoadjuvant chemoradiation in locally advanced rectal cancer markedly improved response to therapy, was well tolerated, and warrants further investigation. Clinical trial information: NCT02688712.

Published
2022

17. Rehabilitation post-COVID-19: cross-sectional observations using the Stanford Hall remote assessment tool

Author

G Wallace, M Martin, K Thompson, Robert M. Barker-Davies, Rhodri Phillip, Mark Cranley, Sarah Lewis, Oliver O’Sullivan, Sardar Bahadur, Michael Gough, and A Segalini

Subjects
medicine.medical_specialty, Telemedicine, Rehabilitation, Coronavirus disease 2019 (COVID-19), business.industry, medicine.medical_treatment, COVID-19, rehabilitation medicine, General Medicine, Logistic regression, Triage, 03 medical and health sciences, 0302 clinical medicine, Mood, Disease severity, Physical therapy, medicine, Anxiety, 030212 general & internal medicine, telemedicine, medicine.symptom, business, 030217 neurology & neurosurgery, Original Research
Abstract

IntroductionThe multisystem COVID-19 can cause prolonged symptoms requiring rehabilitation. This study describes the creation of a remote COVID-19 rehabilitation assessment tool to allow timely triage, assessment and management. It hypotheses those with post-COVID-19 syndrome, potentially without laboratory confirmation and irrespective of initial disease severity, will have significant rehabilitation needs.MethodsCross-sectional study of consecutive patients referred by general practitioners (April–November 2020). Primary outcomes were presence/absence of anticipated sequelae. Binary logistic regression was used to test association between acute presentation and post-COVID-19 symptomatology.Results155 patients (n=127 men, n=28 women, median age 39 years, median 13 weeks post-illness) were assessed using the tool. Acute symptoms were most commonly shortness of breath (SOB) (74.2%), fever (73.5%), fatigue (70.3%) and cough (64.5%); and post-acutely, SOB (76.7%), fatigue (70.3%), cough (57.4%) and anxiety/mood disturbance (39.4%). Individuals with a confirmed diagnosis of COVID-19 were 69% and 63% less likely to have anxiety/mood disturbance and pain, respectively, at 3 months.ConclusionsRehabilitation assessment should be offered to all patients suffering post-COVID-19 symptoms, not only those with laboratory confirmation and considered independently from acute illness severity. This tool offers a structure for a remote assessment. Post-COVID-19 programmes should include SOB, fatigue and mood disturbance management.

Published
2021

18. Explant Modeling of the Immune Environment of Head and Neck Cancer

Author

Shay Sharon, Thomas Duhen, Shelly Bambina, Jason Baird, Rom Leidner, Bryan Bell, Nardy Casap, Marka Crittenden, Swetha Vasudevan, Maria Jubran, Nataly Kravchenko-Balasha, and Michael Gough

Subjects
0301 basic medicine, Cancer Research, Chemokine, tumor, medicine.medical_treatment, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, cytokine, OX40, RC254-282, Original Research, CTLA4, biology, business.industry, Head and neck cancer, explant, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunotherapy, medicine.disease, Head and neck squamous-cell carcinoma, Blockade, PD1, 030104 developmental biology, Cytokine, Oncology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, head and neck cancer, immunotherapy, business, Explant culture
Abstract

Patients exhibit distinct responses to immunotherapies that are thought to be linked to their tumor immune environment. However, wide variations in outcomes are also observed in patients with matched baseline tumor environments, indicating that the biological response to treatment is not currently predictable using a snapshot analysis. To investigate the relationship between the immune environment of tumors and the biological response to immunotherapies, we characterized four murine head and neck squamous cell carcinoma (HNSCC) models on two genetic backgrounds. Using tumor explants from those models, we identified correlations between the composition of infiltrating immune cells and baseline cytokine profiles prior to treatment. Following treatment with PD-1 blockade, CTLA-4 blockade, or OX40 stimulation, we observed inter-individual variability in the response to therapy between genetically identical animals bearing the same tumor. These distinct biological responses to treatment were not linked to the initial tumor immune environment, meaning that outcome would not be predictable from a baseline analysis of the tumor infiltrates. We similarly performed the explant assay on patient HNSCC tumors and found significant variability between the baseline environment of the tumors and their response to therapy. We propose that tumor explants provide a rapid biological assay to assess response to candidate immunotherapies that may allow matching therapies to individual patient tumors. Further development of explant approaches may allow screening and monitoring of treatment responses in HNSCC.

Published
2020

19. Distribution of the superconducting critical current density within a Gd–Ba–Cu–O single grain

Author

Anthony R. Dennis, David A. Cardwell, John H. Durrell, Michael Gough, Yunhua Shi, Shi, Yunhua [0000-0003-4240-5543], Durrell, John H [0000-0003-0712-3102], and Apollo - University of Cambridge Repository

Subjects
Superconductivity, Paper, Materials science, distribution of Jc, porosity, Condensed matter physics, Distribution (number theory), buffer technique, microstructure, Metals and Alloys, Condensed Matter Physics, Microstructure, Focus on Processing and Application of Superconducting Bulk Materials 2019, Materials Chemistry, Ceramics and Composites, Critical current, Electrical and Electronic Engineering, Porosity, GdBCO single grain, Gd-211
Abstract

The magnitude of the maximum trapped magnetic field in a bulk, single-grain superconductor is a key performance figure of merit. This is determined, generally, by the magnitude of the critical current density, J c , and the length scale over which it flows. As with all type-II superconductors, J c is related closely to the microstructure of the superconducting material and, in the case of RE–Ba–Cu–O [(RE)BCO, where RE is a rare-earth element or yttrium] single grains, RE2BaCuO5 (RE-211) inclusions in the superconducting REBa2Cu3O7−δ (RE-123) phase matrix are key microstructural features that act effectively as flux pinning centres. Although the distribution of RE-211 in single-grain bulk superconductors has been studied extensively, the variation of J c within a given sample has been much investigated much less thoroughly. A detailed experimental understanding of the variation of J c in these technologically important materials, therefore, is required given the growing popularity and significance of numerical techniques for modelling the behaviour of type-II bulk superconductors. Here we report a systematic investigation of the correlation between Gd-211 particle density and sample porosity, which are microstructural features, and T c and J c in a Gd–Ba–Cu–O bulk, single grain fabricated using a buffer layer and a supply of additional liquid phase. This was performed by cutting the sample into numerous sub-specimens of approximate dimensions 1.8 × 2.8 × 1.5 mm3. We observe that J c decreases with distance from the seed, although more strongly with distance along the c-axis than along the a–b plane. In contrast to what might be expected given the assumed contribution of RE-211 inclusions to flux pinning, we find no evidence of a clear correlation between the local RE-211 precipitate density and local critical current on a length scale of mm. We observe that the porosity of the sample is a more dominant factor in determining the distribution of J c within a single grain.

Published
2020

21. 'Take-home' box trainers are an effective alternative to virtual reality simulators

Author

Jonathan de Siqueira, Michael Gough, Simon Stock, James S. Tomlinson, Daniel Glassman, and Marina Yiasemidou

Subjects
medicine.medical_specialty, medicine.medical_treatment, Box trainer, Virtual reality, Simulation training, User-Computer Interface, 03 medical and health sciences, 0302 clinical medicine, medicine, Surgical skills, Humans, Computer Simulation, Single-Blind Method, Prospective Studies, 030212 general & internal medicine, Simulation Training, Laparoscopic cholecystectomy, business.industry, United Kingdom, Surgery, Video assessment, Cholecystectomy, Laparoscopic, 030220 oncology & carcinogenesis, Physical therapy, Cholecystectomy, Clinical Competence, business, Clinical skills
Abstract

Background Practice on virtual reality simulators (VRSs) has been shown to improve surgical performance. However, VRSs are expensive and usually housed in surgical skills centers that may be inaccessible at times convenient for surgical trainees to practice. Conversely, box trainers (BT) are inexpensive and can be used anywhere at anytime. This study assesses “take-home” BTs as an alternative to VRS. Methods After baseline assessments (two simulated laparoscopic cholecystectomies, one on a VRS and one on a BT), 25 surgical trainees were randomized to two groups. Trainees were asked to practice three basic laparoscopic tasks for 6 wk (BT group using a “take-home” box trainer; VR group using VRS in clinical skills centers). After the practice period, all performed two laparoscopic cholecystectomy, one on a VRS and one on a BT; (i.e., posttraining assessment). VRS provided metrics (total time [TT], number of movements instrument tip path length), and expert video assessment of cholecystectomy in a BT (Global Operative Assessment of Laparoscopic Skills [GOALS] score) were recorded. Performance during pretraining and posttraining assessment was compared. Results The BT group showed a significant improvement for all VRS metrics (P = 0.008) and the efficiency category of GOALS score (P = 0.03). Only TT improved in the VRS group, and none of the GOALS categories demonstrated a statistically significant improvement after training. Finally, the improvement in VRS metrics in the BT group was significantly greater than in the VR group (TT P = 0.005, number of movements P = 0.042, path length P = 0.031), although there were no differences in the GOALS scores between the groups. Conclusions This study suggests that a basic “take-home” BT is a suitable alternative to VRS.

Published
2017

22. Perceptions About the Present and Future of Surgical Simulation: A National Study of Mixed Qualitative and Quantitative Methodology

Author

James Tomlinson, David Song, Daniel Glassman, Marina Yiasemidou, and Michael Gough

Subjects
Male, Attitude of Health Personnel, media_common.quotation_subject, Specialties, Surgical, Education, Basic skills, 03 medical and health sciences, 0302 clinical medicine, Surveys and Questionnaires, Perception, Humans, Medicine, 030212 general & internal medicine, Simulation Training, Qualitative Research, media_common, Accreditation, Medical education, business.industry, Quantitative methodology, Reproducibility of Results, Quality Improvement, United Kingdom, Cross-Sectional Studies, Evaluation Studies as Topic, 030220 oncology & carcinogenesis, National study, Female, Surgery, Clinical Competence, Surgical education, Surgical simulation, Training program, business
Abstract

Objectives Assess expert opinion on the current and future role of simulation in surgical education. Design Expert opinion was sought through an externally validated questionnaire that was disseminated electronically. Participants Heads of Schools of Surgery (HoS) (and deputies) and Training Program Directors (TPD) (and deputies). Results Simulation was considered a good training tool (HoS: 15/15, TPD: 21/21). The concept that simulation is useful mostly to novices and for basic skills acquisition was rejected (HoS: 15/15, TPDs: 21/21; HoS: 13/15, TPDs: 18/21). Further, simulation is considered suitable for teaching nontechnical skills (HoS: 13/15, TPDs: 20/21) and re-enacting stressful situations (HoS: 14/15, TPDs: 15/21). Most respondents also felt that education centers should be formally accredited (HoS: 12/15, TPDs: 16/21) and that consultant mentors should be appointed by every trust (HoS: 12/15, TPDs: 19/21). In contrast, there were mixed views on its use for trainee assessment (HoS: 6/15, TPDs: 14/21) and whether it should be compulsory (HoS: 8/15, TPDs: 11/21). Conclusion The use of simulation for the acquirement of both technical and nontechnical skills is strongly supported while views on other applications (e.g., assessment) are conflicting. Further, the need for center accreditation and supervised, consultant-led teaching is highlighted.

Published
2017

24. The Stanford Hall coronavirus disease 2019 (COVID-19) remote rehabilitation assessment tool

Author

Sardar Bahadur, Michael Gough, Mark Cranley, Oliver O’Sullivan, Rhodri Phillip, and Robert M. Barker-Davies

Subjects
2019-20 coronavirus outbreak, Rehabilitation, Coronavirus disease 2019 (COVID-19), business.industry, medicine.medical_treatment, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), education, Medicine, Medical rehabilitation, Medical emergency, business, Multidisciplinary team, medicine.disease
Abstract

Coronavirus disease 2019 (COVID-19) is a multisystem illness and can lead to significant morbidity that causes persistent symptoms and functional impairments. In order to assess sequalae and provide rehabilitation services to meet needs of individuals affected, a remote assessment tool was developed in May 2020 by Defence Medical Rehabilitation Centre (DMRC) Stanford Hall personnel. The tool was created by a multidisciplinary team (MDT) working group led by a rehabilitation consultant with a …

Published
2021

25. Correlation between experience targets and competence for general surgery certification

Author

J R De Siqueira and Michael Gough

Subjects
Educational measurement, medicine.medical_specialty, Trainer, medicine.medical_treatment, Certification, 030230 surgery, Correlation, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Competence (human resources), Digestive System Surgical Procedures, Accreditation, Colectomy, business.industry, General surgery, Internship and Residency, United Kingdom, General Surgery, 030220 oncology & carcinogenesis, Surgery, Cholecystectomy, Clinical Competence, Educational Measurement, business
Abstract

Background Working time restrictions and public expectation have stimulated competence-based assessment in surgery. Nevertheless, certification of completion of training, and board accreditation across the developed world, still rely on experiential models based on indicative numbers as markers of operative competence. This study assessed the correlation between trainer assessment of competence and completion of indicative numbers. Methods Analysis of UK Intercollegiate Surgical Curriculum Programme portfolios of general surgical trainees in a single Local Education and Training Board allowed comparison of Procedure Based Assessment (PBA) scores (level of competence) for cholecystectomy, segmental colectomy and Hartmann's procedure with operative numbers. Results Among 121 trainees, there was a positive correlation between operative numbers and 1058 PBA scores for cholecystectomy (rs = 0·532, P < 0·001), segmental colectomy (rs = 0·552, P < 0·001) and Hartmann's procedure (rs= 0·663, P < 0·001). Of those who completed the indicative numbers defined for each procedure to achieve certification of completion of training, only eight of 30 performing cholecystectomy, eight of 52 undertaking segmental colectomy and seven of 36 performing Hartmann's procedure had achieved three PBAs at the level considered to represent independent operating (level 4). More than half of all assessments (259 of 428, 60·5 per cent; 85 of 132 cholecystectomy, 140 of 217 colectomy and 34 of 79 Hartmann's) performed after trainees had completed their indicative numbers were scored below level 4. Conclusion A minimum number of index procedures did not reflect competence in a significant proportion of trainees. A more reliable tool is required for certification.

Published
2016

26. An observational study showed that explaining randomization using gambling-related metaphors and computer-agency descriptions impeded randomized clinical trial recruitment

Author

Marcus Jepson, Daisy Elliott, Carmel Conefrey, Julia Wade, Leila Rooshenas, Caroline Wilson, David Beard, Jane M. Blazeby, Alison Birtle, Alison Halliday, Rob Stein, Jenny L. Donovan, Andrew Carr, Jonathan Cook, Cushla Cooper, Benjamin Dean, Alastair Gray, Stephen Gwilym, Andrew Judge, Naomi Merritt, Jane Moser, Jonathan Rees, Ines Rombach, Julian Savulescu, Irene Tracey, Karolina Wartolowska, Paul Barham, Sara T. Brookes, Tom Crosby, Stephen J. Falk, S. Michael Griffin, William Hollingworth, Andrew D. Hollowood, Richard Krysztopik, Wyn Lewis, Jo Nicklin, Christopher Streets, Sean Strong, Dan Titcomb, Geraint Williams, Rik Bryan, James Catto, John Chester, Ann French, Emma Hall, Chris Harris, Mark Johnson, Rob Jones, Francis Keeley, Tony Kirkbank, Roger Kockelbergh, Rebecca Lewis, Michelle Newton, Thomas Powles, Rachel Waters, Andrew Winterbottom, Jean-Pierre Becquemin, Anna Belli, Marc Bosiers, Piergiorgio Cao, Christina Davies, Michael Gough, Elizabeth Hayter, Peter Leopold, Sumaira McDonald, Jonathan Michaels, Borislava Mihaylova, Richard Peto, Steven Robertson, Peter Rothwell, Rachael Scott, Dafydd Thomas, Frank Vermassen, John Bartlett, David Cameron, Amy Campbell, Peter Canney, Janet Dunn, Helena Earl, Mary Falzon, Adele Francis, Peter Hall, Victoria Harmer, Helen Higgins, Louise Hiller, Luke Hughes-Davies, Claire Hulme, Iain Macpherson, Andreas Makris, Andrea Marshall, Christopher McCabe, Adrienne Morgan, Sarah Pinder, Christopher Poole, Daniel Rea, and Nigel Stallard

Subjects
Randomization, Psychotherapist, Epidemiology, Article, law.invention, 03 medical and health sciences, Random Allocation, 0302 clinical medicine, Randomized controlled trial, Patient Education as Topic, law, Qualitative research, Agency (sociology), Journal Article, Humans, 030212 general & internal medicine, Decision Making, Computer-Assisted, Randomized Controlled Trials as Topic, Random allocation, Patient Selection, United Kingdom, 3. Good health, Comprehension, Patient information, Centre for Surgical Research, 030220 oncology & carcinogenesis, Gambling, CLARITY, Randomized controlled trials, Recruitment to RCTs, Metaphor, Observational study, Recruitment, Psychology
Abstract

Objectives To explore how the concept of randomization is described by clinicians and understood by patients in randomized controlled trials (RCTs) and how it contributes to patient understanding and recruitment. Study Design and Setting Qualitative analysis of 73 audio recordings of recruitment consultations from five, multicenter, UK-based RCTs with identified or anticipated recruitment difficulties. Results One in 10 appointments did not include any mention of randomization. Most included a description of the method or process of allocation. Descriptions often made reference to gambling-related metaphors or similes, or referred to allocation by a computer. Where reference was made to a computer, some patients assumed that they would receive the treatment that was “best for them”. Descriptions of the rationale for randomization were rarely present and often only came about as a consequence of patients questioning the reason for a random allocation. Conclusions The methods and processes of randomization were usually described by recruiters, but often without clarity, which could lead to patient misunderstanding. The rationale for randomization was rarely mentioned. Recruiters should avoid problematic gambling metaphors and illusions of agency in their explanations and instead focus on clearer descriptions of the rationale and method of randomization to ensure patients are better informed about randomization and RCT participation., Highlights • Practices commonly used to describe randomisation in RCT recruitment could confuse patients. • Patients found it difficult to comprehend gambling-related metaphors of randomisation. • Computer-agency descriptions led to patients believing they would receive the best treatment.

Published
2018

27. Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain

Author

Raj P. Kapur, William B. Dobyns, LaRene Kuller, Sean Merillat, Michelle Coleman, Branden R. Nelson, Audrey Baldessari, Kristina M. Adams Waldorf, Kara Jensen, Lakshmi Rajagopal, Kathryn A. Hanley, Jennifer E. Stencel-Baerenwald, Dennis W. W. Shaw, G. Michael Gough, Jeff Thiel, Joseph T. Medwid, Chris Gatenby, Ralph S. Baric, Justin A Roby, W. Mc Intyre Durning, Christie L. Walker, Elyse C. Dewey, Robert F. Hevner, Wonsok Lee, Erica Boldenow, Rebecca D. Hodge, Michael Gale, Jesica Swanstrom, Richard Grant, Michael Davis, Colin Studholme, Junwei Li, Manjiri Dighe, Jennifer Tisoncik-Go, Douglas G. Widman, Chris English, Jason Ogle, Jay Vornhagen, Verónica Santana-Ufret, Marian R. Fairgrieve, Xiaohu Gao, and Blair Armistead

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Microcephaly, Neurogenesis, Immunology, Subventricular zone, Hippocampus, Medical and Health Sciences, Article, General Biochemistry, Genetics and Molecular Biology, Subgranular zone, 03 medical and health sciences, Fetus, Pregnancy, medicine, Animals, Humans, Pregnancy Complications, Infectious, Temporal cortex, biology, business.industry, Animal, Zika Virus Infection, Dentate gyrus, Infectious, Brain, General Medicine, Pigtail macaque, Zika Virus, biology.organism_classification, medicine.disease, 3. Good health, Pregnancy Complications, 030104 developmental biology, medicine.anatomical_structure, nervous system, Gliosis, embryonic structures, Disease Models, Female, medicine.symptom, Macaca nemestrina, business
Abstract

Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque (Macaca nemestrina) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially considerable teratogenic effects of congenital ZIKV infection even without microcephaly. Our findings suggest that all children exposed to ZIKV in utero should receive long-term monitoring for neurocognitive deficits, regardless of head size at birth.

Published
2018

28. Human Embryonic Stem Cell-Derived Cardiomyocytes Regenerate Non-Human Primate Hearts

Author

Benjamin Van Biber, James A. Fugate, Creighton W. Don, Keith W. Vogel, Jay Gantz, Savannah Cook, Hans-Peter Kiem, William M. Mahoney, James J.H. Chong, Lil Pabon, Charles E. Murry, Cliff A. Astley, Yen-Wen Liu, Veronica Nelson, Elina Minami, Nathan J. Palpant, Michael A. Laflamme, Edward A. Gill, G. Michael Gough, Xiulan Yang, Hans Reinecke, Jill J. Weyers, Charlotte E. Hotchkiss, Veronica Muskheli, and Audrey Baldessari

Subjects
0303 health sciences, Multidisciplinary, Regeneration (biology), Anatomy, 030204 cardiovascular system & hematology, Biology, medicine.disease, Embryonic stem cell, Regenerative medicine, Article, Cell biology, Transplantation, 03 medical and health sciences, 0302 clinical medicine, Heart failure, medicine, Myocyte, Myocardial infarction, Induced pluripotent stem cell, health care economics and organizations, 030304 developmental biology
Abstract

Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.

Published
2014

29. Radiofrequency Venous Ablation: Not Simple and Not Always Effective!

Author

Michael Gough

Subjects
business.industry, medicine.medical_treatment, computer.software_genre, Ablation, Text mining, Venous Insufficiency, Catheter Ablation, medicine, Humans, Surgery, Data mining, Cardiology and Cardiovascular Medicine, business, computer, Simple (philosophy)
Published
2019

30. Managing Ash From Municipal Waste Incinerators

Author

Alyce M. Ujihara, Michael Gough, Alyce M. Ujihara, and Michael Gough

Subjects
TD803
Abstract

Originally published in 1989, this report deals with issues surrounding ash residues produced by municipal waste combustors. Spurred by huge disagreements over the environmental risks that these ash residues posed; Managing Ash from Municipal Waste Incinerators attempts to shed light on the debates around the issue and move forward towards an appropriate solution. This title will be of interest to students of Environmental Studies.

Published
2016

31. Group B Streptococcus circumvents neutrophils and neutrophil extracellular traps during amniotic cavity invasion and preterm labor

Author

Michael Gough, Sean Merillat, James W. MacDonald, Lisa Ngo, Claire Gendrin, Craig J. Bierle, Sengkeo L. Srinouanprachanh, Blair Armistead, H. Denny Liggitt, Michelle Coleman, Varchita Alishetti, Erica Boldenow, Aasthaa Bansal, Jay Vornhagen, Christopher Whidbey, Kristina M. Adams Waldorf, Jason Ogle, Verónica Santana-Ufret, Theo K. Bammler, and Lakshmi Rajagopal

Subjects
0301 basic medicine, Pregnancy, Fetus, Amniotic fluid, Immunology, General Medicine, Neutrophil extracellular traps, Biology, medicine.disease, Chorioamnionitis, Article, Microbiology, Sepsis, 03 medical and health sciences, 030104 developmental biology, Immune system, Neutrophil elastase, medicine, biology.protein
Abstract

Preterm birth is a leading cause of neonatal morbidity and mortality. Although microbial invasion of the amniotic cavity (MIAC) is associated with the majority of early preterm births, the temporal events that occur during MIAC and preterm labor are not known. Group B Streptococci (GBS) are β-hemolytic, gram-positive bacteria, which commonly colonize the vagina but have been recovered from the amniotic fluid in preterm birth cases. To understand temporal events that occur during MIAC, we utilized a unique chronically catheterized nonhuman primate model that closely emulates human pregnancy. This model allows monitoring of uterine contractions, timing of MIAC and immune responses during pregnancy-associated infections. Here, we show that adverse outcomes such as preterm labor, MIAC, and fetal sepsis were observed more frequently during infection with hemolytic GBS when compared to nonhemolytic GBS. Although MIAC was associated with systematic progression in chorioamnionitis beginning with chorionic vasculitis and progressing to neutrophilic infiltration, the ability of the GBS hemolytic pigment toxin to induce neutrophil cell death and subvert killing by neutrophil extracellular traps (NETs) in placental membranes in vivo facilitated MIAC and fetal injury. Furthermore, compared to maternal neutrophils, fetal neutrophils exhibit decreased neutrophil elastase activity and impaired phagocytic functions to GBS. Collectively, our studies demonstrate how a unique bacterial hemolytic lipid toxin enables GBS to circumvent neutrophils and NETs in placental membranes to induce fetal injury and preterm labor.

Published
2016

32. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

Author

Casey Ager, Matthew Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin Jaiswal, Michael Curran, Tina C. Albershardt, Anshika Bajaj, Jacob F. Archer, Rebecca S. Reeves, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen, Caroline Denis, Hormas Ghadially, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Robert W. Wilkinson, Nicolai Wagtmann, Yannis Morel, Pascale Andre, Michael B. Atkins, Matteo S. Carlino, Antoni Ribas, John A. Thompson, Toni K. Choueiri, F. Stephen Hodi, Wen-Jen Hwu, David F. McDermott, Victoria Atkinson, Jonathan S. Cebon, Bernie Fitzharris, Michael B. Jameson, Catriona McNeil, Andrew G. Hill, Eric Mangin, Malidi Ahamadi, Marianne van Vugt, Mariëlle van Zutphen, Nageatte Ibrahim, Georgina V. Long, Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Saito, Yingzhi Qian, Yan Lu, Yvonne M. Saenger, Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Kyle Schlunegger, Bruce Freimark, Jeff Hutchins, Christopher A. Barker, Jedd D. Wolchok, Taha Merghoub, Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston, Cristian Capasso, Federica Frascaro, Sara Carpi, Siri Tähtinen, Sara Feola, Manlio Fusciello, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kyruk, Erkko Ylösmäki, Vincenzo Cerullo, Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi, Víctor Cervera-Carrascón, Mikko Siurala, João Santos, Riikka Havunen, Suvi Parviainen, Akseli Hemminki, Angus Dalgleish, Satvinder Mudan, Mark DeBenedette, Ana Plachco, Alicia Gamble, Elizabeth W. Grogan, John Krisko, Irina Tcherepanova, Charles Nicolette, Pooja Dhupkar, Ling Yu, Eugenie S. Kleinerman, Nancy Gordon, Italia Grenga, Lauren Lepone, Sofia Gameiro, Karin M. Knudson, Massimo Fantini, Kwong Tsang, James Hodge, Renee Donahue, Jeffrey Schlom, Elizabeth Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark Paris, Terry Fisher, Siwen Hu-Lieskovan, Ernest Smith, Maurice Zauderer, William Fogler, Marilyn Franklin, Matt Thayer, Dan Saims, John L. Magnani, Jian Gong, Michael Gray, George Fromm, Suresh de Silva, Louise Giffin, Xin Xu, Jason Rose, Taylor H. Schreiber, Sofia R. Gameiro, Paul E. Clavijo, Clint T. Allen, James W. Hodge, Kwong Y. Tsang, Jane Grogan, Nicholas Manieri, Eugene Chiang, Patrick Caplazi, Mahesh Yadav, Patrick Hagner, Hsiling Chiu, Michelle Waldman, Anke Klippel, Anjan Thakurta, Michael Pourdehnad, Anita Gandhi, Ian Henrich, Laura Quick, Rob Young, Margaret Chou, Andrew Hotson, Stephen Willingham, Po Ho, Carmen Choy, Ginna Laport, Ian McCaffery, Richard Miller, Kimberly A. Tipton, Kenneth R. Wong, Victoria Singson, Chihunt Wong, Chanty Chan, Yuanhiu Huang, Shouchun Liu, Jennifer H. Richardson, W. Michael Kavanaugh, James West, Bryan A. Irving, Ritika Jaini, Matthew Loya, Charis Eng, Melissa L. Johnson, Alex A. Adjei, Mateusz Opyrchal, Suresh Ramalingam, Pasi A. Janne, George Dominguez, Dmitry Gabrilovich, Laura de Leon, Jeannette Hasapidis, Scott J. Diede, Peter Ordentlich, Scott Cruickshank, Michael L. Meyers, Matthew D. Hellmann, Pawel Kalinski, Amer Zureikat, Robert Edwards, Ravi Muthuswamy, Nataša Obermajer, Julie Urban, Lisa H. Butterfield, William Gooding, Herbert Zeh, David Bartlett, Olga Zubkova, Larissa Agapova, Marina Kapralova, Liudmila Krasovskaia, Armen Ovsepyan, Maxim Lykov, Artem Eremeev, Vladimir Bokovanov, Olga Grigoryeva, Andrey Karpov, Sergey Ruchko, Alexandr Shuster, Danny N. Khalil, Luis Felipe Campesato, Yanyun Li, Adam S. Lazorchak, Troy D. Patterson, Yueyun Ding, Pottayil Sasikumar, Naremaddepalli Sudarshan, Nagaraj Gowda, Raghuveer Ramachandra, Dodheri Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant, Jasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Birgit Bossenmaier, Gerhard Niederfellner, Yoram Reiter, Ira Pastan, Leiming Xia, Yang Xia, Yangyang Hu, Yi Wang, Yangyi Bao, Fu Dai, Shiang Huang, Elaine Hurt, Robert E. Hollingsworth, Lawrence G. Lum, Alfred E. Chang, Max S. Wicha, Qiao Li, Thomas Mace, Neil Makhijani, Erin Talbert, Gregory Young, Denis Guttridge, Darwin Conwell, Gregory B. Lesinski, Rodney JM Macedo Gonzales, Austin P. Huffman, Ximi K. Wang, Ran Reshef, Andy MacKinnon, Jason Chen, Matt Gross, Gisele Marguier, Peter Shwonek, Natalija Sotirovska, Susanne Steggerda, Francesco Parlati, Amani Makkouk, Mark K. Bennett, Ethan Emberley, Tony Huang, Weiqun Li, Silinda Neou, Alison Pan, Jing Zhang, Winter Zhang, Netonia Marshall, Thomas U. Marron, Judith Agudo, Brian Brown, Joshua Brody, Christopher McQuinn, Matthew Farren, Hannah Komar, Reena Shakya, Thomas Ludwug, Y. Maurice Morillon, Scott A. Hammond, John W. Greiner, Pulak R. Nath, Anthony L. Schwartz, Dragan Maric, David D. Roberts, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Deborah J. Wong, Manish Patel, Gerald Falchook, Shubham Pant, Patrick A. Ott, Melinda Whiteside, Amita Patnaik, John Mumm, Filip Janku, Ivan Chan, Todd Bauer, Rivka Colen, Peter VanVlasselaer, Gail L. Brown, Nizar M. Tannir, Martin Oft, Jeffrey Infante, Evan Lipson, Ajay Gopal, Sattva S. Neelapu, Philippe Armand, Stephen Spurgeon, John P. Leonard, Rachel E. Sanborn, Ignacio Melero, Thomas F. Gajewski, Matthew Maurer, Serena Perna, Andres A. Gutierrez, Raphael Clynes, Priyam Mitra, Satyendra Suryawanshi, Douglas Gladstone, Margaret K. Callahan, James Crooks, Sheila Brown, Audrey Gauthier, Marc Hillairet de Boisferon, Andrew MacDonald, Laura Rosa Brunet, William T. Rothwell, Peter Bell, James M. Wilson, Fumi Sato-Kaneko, Shiyin Yao, Shannon S. Zhang, Dennis A. Carson, Cristina Guiducci, Robert L. Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Tomoko Hayashi, Ezra E. W. Cohen, David Schaer, Yanxia Li, Julie Dobkin, Michael Amatulli, Gerald Hall, Thompson Doman, Jason Manro, Frank Charles Dorsey, Lillian Sams, Rikke Holmgaard, Krishnadatt Persaud, Dale Ludwig, David Surguladze, John S. Kauh, Ruslan Novosiadly, Michael Kalos, Kyla Driscoll, Hardev Pandha, Christy Ralph, Kevin Harrington, Brendan Curti, Wallace Akerley, Sumati Gupta, Alan Melcher, David Mansfield, David R. Kaufman, Emmett Schmidt, Mark Grose, Bronwyn Davies, Roberta Karpathy, Darren Shafren, Katerina Shamalov, Cyrille Cohen, Naveen Sharma, James Allison, Tala Shekarian, Sandrine Valsesia-Wittmann, Christophe Caux, Aurelien Marabelle, Brian M. Slomovitz, Kathleen M. Moore, Hagop Youssoufian, Marshall Posner, Poonam Tewary, Alan D. Brooks, Ya-Ming Xu, Kithsiri Wijeratne, Leslie A. A. Gunatilaka, Thomas J. Sayers, John P. Vasilakos, Tesha Alston, Simon Dovedi, James Elvecrog, Iwen Grigsby, Ronald Herbst, Karen Johnson, Craig Moeckly, Stefanie Mullins, Kristen Siebenaler, Julius SternJohn, Ashenafi Tilahun, Mark A. Tomai, Katharina Vogel, Eveline E. Vietsch, Anton Wellstein, Martin Wythes, Stefano Crosignani, Joseph Tumang, Shilpa Alekar, Patrick Bingham, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, JunLi Feng, Kim Frederix, Samantha Greasley, Jie Guo, James Hardwick, Stephen Kaiser, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Kevin Ryan, Stephanie Scales, Jay Srirangam, Jim Solowiej, Al Stewart, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Xianxian Zheng, Gregory Driessens, Bruno Gomes, Manfred Kraus, Chunxiao Xu, Yanping Zhang, Giorgio Kradjian, Guozhong Qin, Jin Qi, Xiaomei Xu, Bo Marelli, Huakui Yu, Wilson Guzman, Rober Tighe, Rachel Salazar, Kin-Ming Lo, Jessie English, Laszlo Radvanyi, Yan Lan, Michael Postow, Yasin Senbabaoglu, Billel Gasmi, Hong Zhong, Cailian Liu, Daniel Hirschhorhn-Cymerman, Yuanyuan Zha, Gregory Malnassy, Noreen Fulton, Jae-Hyun Park, Wendy Stock, Yusuke Nakamura, Hongtao Liu, Xiaoming Ju, Rachelle Kosoff, Kimberly Ramos, Brandon Coder, Robert Petit, Michael Princiotta, Kyle Perry, Jun Zou, Ainhoa Arina, Christian Fernandez, Wenxin Zheng, Michael A. Beckett, Helena J. Mauceri, Yang-Xin Fu, Ralph R. Weichselbaum, Whitney Lewis, Yanyan Han, Yeting Wu, Chou Yang, Jing Huang, Dongyun Wu, Jin Li, Xiaoling Liang, Xiangjun Zhou, Jinlin Hou, Raffit Hassan, Thierry Jahan, Scott J. Antonia, Hedy L. Kindler, Evan W. Alley, Somayeh Honarmand, Weiqun Liu, Meredith L. Leong, Chan C. Whiting, Nitya Nair, Amanda Enstrom, Edward E. Lemmens, Takahiro Tsujikawa, Sushil Kumar, Lisa M. Coussens, Aimee L. Murphy, Dirk G. Brockstedt, Sven D. Koch, Martin Sebastian, Christian Weiss, Martin Früh, Miklos Pless, Richard Cathomas, Wolfgang Hilbe, Georg Pall, Thomas Wehler, Jürgen Alt, Helge Bischoff, Michael Geissler, Frank Griesinger, Jens Kollmeier, Alexandros Papachristofilou, Fatma Doener, Mariola Fotin-Mleczek, Madeleine Hipp, Henoch S. Hong, Karl-Josef Kallen, Ute Klinkhardt, Claudia Stosnach, Birgit Scheel, Andreas Schroeder, Tobias Seibel, Ulrike Gnad-Vogt, Alfred Zippelius, Ha-Ram Park, Yong-Oon Ahn, Tae Min Kim, Soyeon Kim, Seulki Kim, Yu Soo Lee, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Shari Pilon-Thomas, Amy Weber, Jennifer Morse, Krithika Kodumudi, Hao Liu, John Mullinax, Amod A. Sarnaik, Luke Pike, Andrew Bang, Tracy Balboni, Allison Taylor, Alexander Spektor, Tyler Wilhite, Monica Krishnan, Daniel Cagney, Brian Alexander, Ayal Aizer, Elizabeth Buchbinder, Mark Awad, Leena Ghandi, Jonathan Schoenfeld, Elizabeth Lessey-Morillon, Lisa Ridnour, Neil H. Segal, Manish Sharma, Dung T. Le, Robert L. Ferris, Andrew D. Zelenetz, Ronald Levy, Izidore S. Lossos, Caron Jacobson, Radhakrishnan Ramchandren, John Godwin, A. Dimitrios Colevas, Roland Meier, Suba Krishnan, Xuemin Gu, Jaclyn Neely, John Timmerman, Claire I. Vanpouille-Box, Silvia C. Formenti, Sandra Demaria, Erik Wennerberg, Aranzazu Mediero, Bruce N. Cronstein, Michael P. Gustafson, AriCeli DiCostanzo, Courtney Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A. Gastineau, Bruce D. Johnson, Allan B. Dietz, Cameron MacDonald, Mark Bucsek, Guanxi Qiao, Bonnie Hylander, Elizabeth Repasky, William J. Turbitt, Yitong Xu, Andrea Mastro, Connie J. Rogers, Sita Withers, Ziming Wang, Lam T. Khuat, Cordelia Dunai, Bruce R. Blazar, Dan Longo, Robert Rebhun, Steven K. Grossenbacher, Arta Monjazeb, William J. Murphy, Scott Rowlinson, Giulia Agnello, Susan Alters, David Lowe, Nicole Scharping, Ashley V. Menk, Ryan Whetstone, Xue Zeng, Greg M. Delgoffe, Patricia M. Santos, Jian Shi, Greg Delgoffe, Misako Nagasaka, Ammar Sukari, Miranda Byrne-Steele, Wenjing Pan, Xiaohong Hou, Brittany Brown, Mary Eisenhower, Jian Han, Natalie Collins, Robert Manguso, Hans Pope, Yashaswi Shrestha, Jesse Boehm, W. Nicholas Haining, Kyle R. Cron, Ayelet Sivan, Keston Aquino-Michaels, Marco Orecchioni, Davide Bedognetti, Wouter Hendrickx, Claudia Fuoco, Filomena Spada, Francesco Sgarrella, Gianni Cesareni, Francesco Marincola, Kostas Kostarelos, Alberto Bianco, Lucia Delogu, Jessica Roelands, Sabri Boughorbel, Julie Decock, Scott Presnell, Ena Wang, Franco M. Marincola, Peter Kuppen, Michele Ceccarelli, Darawan Rinchai, Damien Chaussabel, Lance Miller, Andrew Nguyen, J. Zachary Sanborn, Charles Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Steven Benz, Shashank Patel, Nicholas Restifo, James White, Sam Angiuoli, Mark Sausen, Sian Jones, Maria Sevdali, John Simmons, Victor Velculescu, Luis Diaz, Theresa Zhang, Jennifer S. Sims, Sunjay M. Barton, Angela Kadenhe-Chiweshe, Filemon Dela Cruz, Andrew T. Turk, Christopher F. Mazzeo, Andrew L. Kung, Jeffrey N. Bruce, Darrell J. Yamashiro, Eileen P. Connolly, Jason Baird, Marka Crittenden, David Friedman, Hong Xiao, Rom Leidner, Bryan Bell, Kristina Young, Michael Gough, Zhen Bian, Koby Kidder, Yuan Liu, Emily Curran, Xiufen Chen, Leticia P. Corrales, Justin Kline, Ethan G. Aguilar, Jennifer Guerriero, Alaba Sotayo, Holly Ponichtera, Alexandra Pourzia, Sara Schad, Ruben Carrasco, Suzan Lazo, Roderick Bronson, Anthony Letai, Richard S. Kornbluth, Sachin Gupta, James Termini, Elizabeth Guirado, Geoffrey W. Stone, Christina Meyer, Laura Helming, Nicholas Wilson, Robert Hofmeister, Natalie J. Neubert, Laure Tillé, David Barras, Charlotte Soneson, Petra Baumgaertner, Donata Rimoldi, David Gfeller, Mauro Delorenzi, Silvia A. Fuertes Marraco, Daniel E. Speiser, Tara S. Abraham, Bo Xiang, Michael S. Magee, Scott A. Waldman, Adam E. Snook, Wojciech Blogowski, Ewa Zuba-Surma, Marta Budkowska, Daria Salata, Barbara Dolegowska, Teresa Starzynska, Leo Chan, Srinivas Somanchi, Kelsey McCulley, Dean Lee, Nico Buettner, Feng Shi, Paisley T. Myers, Stuart Curbishley, Sarah A. Penny, Lora Steadman, David Millar, Ellen Speers, Nicola Ruth, Gabriel Wong, Robert Thimme, David Adams, Mark Cobbold, Remy Thomas, Mariam Al-Muftah, Michael KK Wong, Michael Morse, Joseph I. Clark, Howard L. Kaufman, Gregory A. Daniels, Hong Hua, Tharak Rao, Janice P. Dutcher, Kai Kang, Yogen Saunthararajah, Vamsidhar Velcheti, Vikas Kumar, Firoz Anwar, Amita Verma, Zinal Chheda, Gary Kohanbash, John Sidney, Kaori Okada, Shruti Shrivastav, Diego A. Carrera, Shuming Liu, Naznin Jahan, Sabine Mueller, Ian F. Pollack, Angel M. Carcaboso, Alessandro Sette, Yafei Hou, Hideho Okada, Jessica J. Field, Weiping Zeng, Vincent FS Shih, Che-Leung Law, Peter D. Senter, Shyra J. Gardai, Nicole M. Okeley, Jennifer G. Abelin, Abu Z. Saeed, Stacy A. Malaker, Jeffrey Shabanowitz, Stephen T. Ward, Donald F. Hunt, Pam Profusek, Laura Wood, Dale Shepard, Petros Grivas, Kerstin Kapp, Barbara Volz, Detlef Oswald, Burghardt Wittig, Manuel Schmidt, Julian P. Sefrin, Lars Hillringhaus, Valeria Lifke, Alexander Lifke, Anna Skaletskaya, Jose Ponte, Thomas Chittenden, Yulius Setiady, Eva Sivado, Vincent Thomas, Meddy El Alaoui, Sébastien Papot, Charles Dumontet, Mike Dyson, John McCafferty, Said El Alaoui, Praveen K. Bommareddy, Andrew Zloza, Frederick Kohlhapp, Ann W. Silk, Sachin Jhawar, Tomas Paneque, Jenna Newman, Pedro Beltran, Felicia Cao, Bang-Xing Hong, Tania Rodriguez-Cruz, Xiao-Tong Song, Stephen Gottschalk, Hugo Calderon, Sam Illingworth, Alice Brown, Kerry Fisher, Len Seymour, Brian Champion, Emma Eriksson, Jessica Wenthe, Ann-Charlotte Hellström, Gabriella Paul-Wetterberg, Angelica Loskog, Ioanna Milenova, Magnus Ståhle, Justyna Jarblad-Leja, Gustav Ullenhag, Anna Dimberg, Rafael Moreno, Ramon Alemany, Sharad Goyal, Ann Silk, Janice Mehnert, Nashat Gabrail, Jennifer Bryan, Daniel Medina, Leah Mitchell, Kader Yagiz, Fernando Lopez, Daniel Mendoza, Anthony Munday, Harry Gruber, Douglas Jolly, Steven Fuhrmann, Sasa Radoja, Wei Tan, Aldo Pourchet, Alan Frey, Ian Mohr, Matthew Mulvey, Robert H. I. Andtbacka, Merrick Ross, Sanjiv Agarwala, Kenneth Grossmann, Matthew Taylor, John Vetto, Rogerio Neves, Adil Daud, Hung Khong, Stephanie M. Meek, Richard Ungerleider, Scott Welden, Maki Tanaka, Matthew Williams, Sigrun Hallmeyer, Bernard Fox, Zipei Feng, Christopher Paustian, Carlo Bifulco, Sadia Zafar, Otto Hemminki, Simona Bramante, Lotta Vassilev, Hongjie Wang, Andre Lieber, Silvio Hemmi, Tanja de Gruijl, Anna Kanerva, Tameem Ansari, Srividya Sundararaman, Diana Roen, Paul Lehmann, Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Jay A. Berzofsky, Fanny Chapelin, Eric T. Ahrens, Jeff DeFalco, Michael Harbell, Amy Manning-Bog, Alexander Scholz, Danhui Zhang, Gilson Baia, Yann Chong Tan, Jeremy Sokolove, Dongkyoon Kim, Kevin Williamson, Xiaomu Chen, Jillian Colrain, Gregg Espiritu Santo, Ngan Nguyen, Wayne Volkmuth, Norman Greenberg, William Robinson, Daniel Emerling, Charles G. Drake, Daniel P. Petrylak, Emmanuel S. Antonarakis, Adam S. Kibel, Nancy N. Chang, Tuyen Vu, Dwayne Campogan, Heather Haynes, James B. Trager, Nadeem A. Sheikh, David I. Quinn, Peter Kirk, Murali Addepalli, Thomas Chang, Ping Zhang, Marina Konakova, Katsunobu Hagihara, Steven Pai, Laurie VanderVeen, Palakshi Obalapur, Peiwen Kuo, Phi Quach, Lawrence Fong, Deborah H. Charych, Jonathan Zalevsky, John L. Langowski, Yolanda Kirksey, Ravi Nutakki, Shalini Kolarkar, Rhoneil Pena, Ute Hoch, Stephen K. Doberstein, John Cha, Zach Mallon, Myra Perez, Amanda McDaniel, Snjezana Anand, Darrin Uecker, Richard Nuccitelli, Eva Wieckowski, Ravikumar Muthuswamy, Roshni Ravindranathan, Ariana N. Renrick, Menaka Thounaojam, Portia Thomas, Samuel Pellom, Anil Shanker, Duafalia Dudimah, Alan Brooks, Yu-Lin Su, Tomasz Adamus, Qifang Zhang, Sergey Nechaev, Marcin Kortylewski, Spencer Wei, Clark Anderson, Chad Tang, Jonathan Schoenhals, Efrosini Tsouko, John Heymach, Patricia de Groot, Joe Chang, Kenneth R. Hess, Adi Diab, Padmanee Sharma, David Hong, James Welsh, Andrea J. Parsons, Jardin Leleux, Stephane Ascarateil, Marie Eve Koziol, Dina Bai, Peihong Dai, Weiyi Wang, Ning Yang, Stewart Shuman, Liang Deng, Patrick Dillon, Gina Petroni, David Brenin, Kim Bullock, Walter Olson, Mark E. Smolkin, Kelly Smith, Carmel Nail, Craig L. Slingluff, Meenu Sharma, Faisal Fa’ak, Louise Janssen, Hiep Khong, Zhilan Xiao, Yared Hailemichael, Manisha Singh, Christina Vianden, Willem W. Overwijk, Andrea Facciabene, Pierini Stefano, Fang Chongyung, Stavros Rafail, Michael Nielsen, Peter Vanderslice, Darren G. Woodside, Robert V. Market, Ronald J. Biediger, Upendra K. Marathi, Kevin Hollevoet, Nick Geukens, Paul Declerck, Nathalie Joly, Laura McIntosh, Eustache Paramithiotis, Magnus Rizell, Malin Sternby, Bengt Andersson, Alex Karlsson-Parra, Rui Kuai, Lukasz Ochyl, Anna Schwendeman, James Moon, Weiwen Deng, Thomas E. Hudson, Bill Hanson, Chris S. Rae, Joel Burrill, Justin Skoble, George Katibah, Michele deVries, Peter Lauer, Thomas W. Dubensky, Xin Chen, Li Zhou, Xiubao Ren, Charu Aggarwal, Drishty Mangrolia, Roger Cohen, Gregory Weinstein, Matthew Morrow, Joshua Bauml, Kim Kraynyak, Jean Boyer, Jian Yan, Jessica Lee, Laurent Humeau, Sandra Oyola, Susan Duff, David Weiner, Zane Yang, Mark Bagarazzi, Douglas G. McNeel, Jens Eickhoff, Robert Jeraj, Mary Jane Staab, Jane Straus, Brian Rekoske, Glenn Liu, Marit Melssen, William Grosh, Nikole Varhegyi, Nadejda Galeassi, Donna H. Deacon, Elizabeth Gaughan, Maurizio Ghisoli, Minal Barve, Robert Mennel, Gladice Wallraven, Luisa Manning, Neil Senzer, John Nemunaitis, Masahiro Ogasawara, Shuichi Ota, Kaitlin M. Peace, Diane F. Hale, Timothy J. Vreeland, Doreen O. Jackson, John S. Berry, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, Anne Toms, Na Qiao, Jennifer Litton, George E. Peoples, Elizabeth A. Mittendorf, Lila Ghamsari, Emilio Flano, Judy Jacques, Biao Liu, Jonathan Havel, Vladimir Makarov, Timothy A. Chan, Jessica B. Flechtner, John Facciponte, Stefano Ugel, Francesco De Sanctis, George Coukos, Sébastien Paris, Agnes Pottier, Laurent Levy, Bo Lu, Federica Cappuccini, Emily Pollock, Richard Bryant, Freddie Hamdy, Adrian Hill, Irina Redchenko, Hussein Sultan, Takumi Kumai, Valentyna Fesenkova, Esteban Celis, Ingrid Fernando, Claudia Palena, Justin M. David, Elizabeth Gabitzsch, Frank Jones, James L. Gulley, Mireia Uribe Herranz, Hiroshi Wada, Atsushi Shimizu, Toshihiro Osada, Satoshi Fukaya, Eiji Sasaki, Milad Abolhalaj, David Askmyr, Kristina Lundberg, Ann-Sofie Albrekt, Lennart Greiff, Malin Lindstedt, Dallas B. Flies, Tomoe Higuchi, Wojciech Ornatowski, Jaryse Harris, Sarah F. Adams, Todd Aguilera, Marjan Rafat, Laura Castellini, Hussein Shehade, Mihalis Kariolis, Dadi Jang, Rie vonEbyen, Edward Graves, Lesley Ellies, Erinn Rankin, Albert Koong, Amato Giaccia, Reham Ajina, Shangzi Wang, Jill Smith, Mariaelena Pierobon, Sandra Jablonski, Emanuel Petricoin, Louis M. Weiner, Lorcan Sherry, John Waller, Mark Anderson, Alison Bigley, Chantale Bernatchez, Cara Haymaker, Harriet Kluger, Michael Tetzlaff, Natalie Jackson, Ivan Gergel, Mary Tagliaferri, Patrick Hwu, Mario Snzol, Michael Hurwitz, Theresa Barberi, Allison Martin, Rahul Suresh, David Barakat, Sarah Harris-Bookman, Charles Drake, Alan Friedman, Sara Berkey, Stephanie Downs-Canner, Robert P. Edwards, Tyler Curiel, Kunle Odunsi, Tullia C. Bruno, Brandon Moore, Olivia Squalls, Peggy Ebner, Katherine Waugh, John Mitchell, Wilbur Franklin, Daniel Merrick, Martin McCarter, Brent Palmer, Jeffrey Kern, Dario Vignali, Jill Slansky, Anissa S. H. Chan, Xiaohong Qiu, Kathryn Fraser, Adria Jonas, Nadine Ottoson, Keith Gordon, Takashi O. Kangas, Steven Leonardo, Kathleen Ertelt, Richard Walsh, Mark Uhlik, Jeremy Graff, Nandita Bose, Ravi Gupta, Nitin Mandloi, Kiran Paul, Ashwini Patil, Rekha Sathian, Aparna Mohan, Malini Manoharan, Amitabha Chaudhuri, Yu Chen, Jing Lin, Yun-bin Ye, Chun-wei Xu, Gang Chen, Zeng-qing Guo, Andrey Komarov, Alex Chenchik, Michael Makhanov, Costa Frangou, Yi Zheng, Carla Coltharp, Darryn Unfricht, Ryan Dilworth, Leticia Fridman, Linying Liu, Milind Rajopadhye, Peter Miller, Fernando Concha-Benavente, Julie Bauman, Sumita Trivedi, Raghvendra Srivastava, James Ohr, Dwight Heron, Uma Duvvuri, Seungwon Kim, Heather Torrey, Toshi Mera, Yoshiaki Okubo, Eva Vanamee, Rosemary Foster, Denise Faustman, Edward Stack, Daisuke Izaki, Kristen Beck, Dan Tong Jia, Paul Armenta, Ashley White-Stern, Douglas Marks, Bret Taback, Basil Horst, Laura Hix Glickman, David B. Kanne, Kelsey S. Gauthier, Anthony L. Desbien, Brian Francica, Justin L. Leong, Leonard Sung, Ken Metchette, Shailaja Kasibhatla, Anne Marie Pferdekamper, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, John Tallarico, Steven Bender, Chudi Ndubaku, Sarah M. McWhirter, Elena Gonzalez Gugel, Charles J. M. Bell, Adiel Munk, Luciana Muniz, Nina Bhardwaj, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nathalie Scholler, Catherine Yin, Pien Van der Meijs, Andrew M. Prantner, Cecile M. Krejsa, Leia Smith, Brian Johnson, Daniel Branstetter, Paul L. Stein, Juan C. Jaen, Joanne BL Tan, Ada Chen, Timothy Park, Jay P. Powers, Holly Sexton, Guifen Xu, Steve W. Young, Ulrike Schindler, Wentao Deng, David John Klinke, Hannah M. Komar, Gregory Serpa, Omar Elnaggar, Philip Hart, Carl Schmidt, Mary Dillhoff, Ming Jin, Michael C. Ostrowski, Madhuri Koti, Katrina Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Charles Graham, Andrew Craig, Julie-Ann Francis, Beatrix Kotlan, Timea Balatoni, Emil Farkas, Laszlo Toth, Mihaly Ujhelyi, Akos Savolt, Zoltan Doleschall, Szabolcs Horvath, Klara Eles, Judit Olasz, Orsolya Csuka, Miklos Kasler, Gabriella Liszkay, Eytan Barnea, Collin Blakely, Patrick Flynn, Reid Goodman, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Brian West, Paul R. Kunk, Joseph M. Obeid, Kevin Winters, Patcharin Pramoonjago, Edward B. Stelow, Todd W. Bauer, Osama E. Rahma, Adam Lamble, Yoko Kosaka, Fei Huang, Kate A. Saser, Homer Adams, Christina E. Tognon, Ted Laderas, Shannon McWeeney, Marc Loriaux, Jeffery W. Tyner, Brian J. Druker, Evan F. Lind, Zhuqing Liu, Shanhong Lu, Lawrence P. Kane, Gulidanna Shayan, Julia Femel, Ryan Lane, Jamie Booth, Amanda W. Lund, Anthony Rodriguez, Victor H. Engelhard, Alessandra Metelli, Bill X. Wu, Caroline W. Fugle, Rachidi Saleh, Shaoli Sun, Jennifer Wu, Bei Liu, Zihai Li, Zachary S. Morris, Emily I. Guy, Clinton Heinze, Jasdeep Kler, Monica M. Gressett, Lauryn R. Werner, Stephen D. Gillies, Alan J. Korman, Hans Loibner, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Erica Huelsmann, Joseph Broucek, Dorothee Brech, Tobias Straub, Martin Irmler, Johannes Beckers, Florian Buettner, Elke Schaeffeler, Matthias Schwab, Elfriede Noessner, Alison Wolfreys, Andre Da Costa, John Silva, Andrea Crosby, Ludovicus Staelens, Graham Craggs, Annick Cauvin, Sean Mason, Alison M. Paterson, Andrew C. Lake, Caroline M. Armet, Rachel W. O’Connor, Jonathan A. Hill, Emmanuel Normant, Ammar Adam, Detlev M. Biniszkiewicz, Scott C. Chappel, Vito J. Palombella, Pamela M. Holland, Annette Becker, Manmohan R. Leleti, Eric Newcomb, Joanne B. L. Tan, Suthee Rapisuwon, Arash Radfar, Kellie Gardner, Geoffrey Gibney, Michael Atkins, Keith R. Rennier, Robert Crowder, Ping Wang, Russell K. Pachynski, Rosa M. Santana Carrero, Sarai Rivas, Figen Beceren-Braun, Scott Anthony, Kimberly S. Schluns, Deepali Sawant, Maria Chikina, Hiroshi Yano, Creg Workman, Elise Salerno, Ileana Mauldin, Donna Deacon, Sofia Shea, Joel Pinczewski, Thomas Gajewski, Stefani Spranger, Brendan Horton, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri, Randy F. Sweis, Riyue Bao, Jason Luke, Marie-Nicole Theodoraki, Frances-Mary Mogundo, Haejung Won, Dayson Moreira, Chan Gao, Xingli Zhao, Priyanka Duttagupta, Jeremy Jones, Massimo D’Apuzzo, and Sumanta Pal

Subjects
0301 basic medicine, Pharmacology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Cancer, Immunotherapy, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, Molecular Medicine, Immunology and Allergy, Medicine, business
Abstract

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Published
2016

33. Non-atherosclerotic carotid disease

Author

Michael Gough and Andy Kordowicz

Subjects
medicine.medical_specialty, business.industry, Internal medicine, Cardiology, Medicine, Disease, business
Published
2016

34. Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate

Author

Chris English, Marian R. Fairgrieve, J. Christopher Gatenby, Gwenn A. Garden, Sean Merillat, Jeff Thiel, Robert F. Hevner, Jason Ogle, Wonsok Lee, Erica Boldenow, Colin Studholme, Lakshmi Rajagopal, Jay Vornhagen, Michael S. Diamond, Blair Armistead, Michael Gale, Dennis W. W. Shaw, Raj P. Kapur, Michael Davis, G. Michael Gough, William B. Dobyns, Todd L. Richards, Jennifer E. Stencel-Baerenwald, Audrey Baldessari, Kristina M. Adams Waldorf, La Rene Kuller, Richard Green, Sandra E. Juul, Richard Grant, Manjiri Dighe, Elyse C. Dewey, and Jennifer Tisoncik-Go

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Glutamine, Glutamic Acid, Autopsy, Biology, General Biochemistry, Genetics and Molecular Biology, Ultrasonography, Prenatal, Article, Zika virus, Choline, 03 medical and health sciences, Fetus, Pregnancy, medicine, Animals, Pregnancy Complications, Infectious, Aspartic Acid, medicine.diagnostic_test, Zika Virus Infection, Brain, Magnetic resonance imaging, General Medicine, Pigtail macaque, Zika Virus, biology.organism_classification, Creatine, Echoencephalography, Magnetic Resonance Imaging, 030104 developmental biology, Gliosis, Cerebral white matter hypoplasia, RNA, Viral, Female, medicine.symptom, Macaca nemestrina, Inositol
Abstract

We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital-parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.

Published
2016

35. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic

Author

Roma Yumul, Hongjie Wang, Michael Gough, Darrick Carter, Haishan Jang, André Lieber, Audrey Baldessari, Roberto Cattaneo, Anne Astier, Ajay K. Gopal, Frank Lee, Chung Huei Katherine Wang, Maximilian Richter, Kamola Saydaminova, Division of Medical Genetics [Seattle], University of Washington [Seattle], Washington National Primate Research Center [Seattle], Molecular Medicine Program, Mayo Clinic, Department of chemical Engineering, Yuan-Ze University, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Health and Safety Executive

Subjects
0301 basic medicine, Biodistribution, lcsh:QH426-470, medicine.drug_class, Pharmacology, Monoclonal antibody, Article, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Genetics, Medicine, lcsh:QH573-671, Molecular Biology, ComputingMilieux_MISCELLANEOUS, CD20, biology, business.industry, CD46, lcsh:Cytology, Immunogenicity, 3. Good health, lcsh:Genetics, 030104 developmental biology, biology.protein, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, business, Protein A, 030215 immunology, medicine.drug
Abstract

Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs). The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs) with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with rituximab in the treatment of patients with B-cell malignancies.

Published
2016

36. Re-analysis of Ranch Hand study supports reverse causation hypothesis between dioxin and diabetes

Author

Brent D. Kerger, Michael Gough, Paul Scott, Dennis J. Paustenbach, and Marian Pavuk

Subjects
medicine.medical_specialty, Polychlorinated Dibenzodioxins, Diabetes risk, Databases, Factual, Physiology, Toxicology, Body Mass Index, Vietnam Conflict, chemistry.chemical_compound, Risk Factors, Internal medicine, Diabetes mellitus, Diabetes Mellitus, Odds Ratio, medicine, Humans, heterocyclic compounds, Veterans, Incidence, Agent Orange, Incidence (epidemiology), Environmental Exposure, Environmental exposure, Odds ratio, medicine.disease, Obesity, United States, Endocrinology, chemistry, Environmental Pollutants, Body mass index, Half-Life
Abstract

A dose-response relationship between serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and adult diabetes risk has been reported among U.S. Vietnam veterans in the Ranch Hand (RH) cohort. We examine the hypothesis that diabetes progression leads to higher serum dioxin (reverse causation) rather than higher serum dioxin leading to diabetes (causation) across the longitudinal medical monitoring data on these airmen. Lipid-adjusted serum dioxin levels and clinical parameters relating to diabetes progression were examined. Potential confounding due to age, race, diabetes family history, serum total lipid, and body mass index (BMI) was accounted for. The similar incidence of diabetes in RH and Comparison veterans, along with generally similar incidence trends with dioxin decile and lipid decile despite the large differential in serum dioxin, is evidence consistent with reverse causation. Of 135 RH diabetics with at least two dioxin measurements, 32.6% had a temporary serum dioxin increase more than a decade after Vietnam tour and another 22.2% had an interval of unusually slow half-life (>15.5 years); these diabetes-related changes shifted more diabetics into the higher dioxin deciles. Further, the increased diabetes odds ratio among the generally younger RH veterans in the highest dioxin decile is associated with a higher incidence of adult obesity in this RH subgroup, both at tour of duty and decades later. Change in serum dioxin levels is likely due to diabetes progression or poor control and is not independently related to serum dioxin concentrations. In summary, the data from the Ranch Hand studies does not indicate that dioxin increases adult diabetes risk.

Published
2012

37. Anti-tumor immunity generated as an artifact of tumor implantation determines the response to immunotherapy in murine models

Author

Michael Gough, Zebertavage, Lauren, Bambina, Shelly, Kramer, Gwen, Friedman, David J., Troesch, Victoria, Blair, Tiffany, Baird, Jason R., Alice, Alejandro, and Crittenden, Marka R.

Subjects
Immunology, Immunology and Allergy
Abstract

Cancer cell lines grown in vitro and implanted into mice are a centerpiece of preclinical modeling. However, tumor implantation is an in vivo vaccination event that can impact tumor growth. Checkpoint inhibitors targeting PD1 or CTLA4 interactions are effective at unleashing suppressed pre-existing immunity in murine models, but do not generate new immune responses. We hypothesized that tumor control by checkpoint inhibitor immunotherapies was dependent on pre-existing immunity generated at tumor implantation. Using cancer cells engineered to express model antigens, spontaneous tumor models with defined trackable antigens, or unmodified cancer cells, we demonstrate that tumor implantation results in initial T cell mediated immunity. As the tumors progress, these cells become undetectable in the periphery and accumulate in the tumor, but do not prevent tumor progression. While tumors respond to checkpoint inhibitors administered closely following implantation, delayed administration results in a loss of efficacy. This efficacy can be recovered by the addition of radiation therapy to checkpoint inhibitors, permitting cure of established murine tumors that are not controlled by either therapy alone. However, blocking the immune response at tumor implantation using a range of approaches results in a complete loss of efficacy of tumor control by all therapies based around checkpoint inhibitors. We demonstrate an approach to ‘silently’ establish tumors in mice to test therapies that can initiate de novo immunity to tumors. These data have significant implications for current clinical attempts to use checkpoint inhibitors, which may not be a solution for patients without pre-existing immunity to their tumor.

Published
2018

40. Successful outcomes following neurorehabilitation in military traumatic brain injury patients in the United Kingdom

Author

Jennifer Duncan-Anderson, Shreshth Dharm-Datta, John Etherington, Elizabeth Olivier, Michael Gough, Emer McGilloway, and Patrick J. Porter

Subjects
Adult, Male, medicine.medical_specialty, Traumatic brain injury, medicine.medical_treatment, Standard score, Critical Care and Intensive Care Medicine, Disability Evaluation, medicine, Humans, Glasgow Coma Scale, Prospective Studies, Acquired brain injury, Neurorehabilitation, Rehabilitation, business.industry, Neurological Rehabilitation, Evidence-based medicine, Recovery of Function, medicine.disease, Prognosis, Confidence interval, United Kingdom, Military Personnel, Brain Injuries, Physical therapy, Surgery, Female, business, Independent living
Abstract

BACKGROUND The Defence Medical Rehabilitation Centre Headley Court is the UK military rehabilitation unit. A pilot study identified the Mayo-Portland Adaptability Inventory-4 (MPAI-4) as the most appropriate rehabilitation outcome measure in young military patients with acquired brain injury. METHODS MPAI-4 scores were prospectively recorded for patients on admission and discharge. At 4 months, independent living and employment status were recorded. Inclusion criteria were all new admissions with traumatic brain injury (TBI). Before injury, all patients were fully employed and lived independently. RESULTS In a 3-year period from April 2011, there were 91 TBI patients with complete admission-discharge episodes: by US Department of Defense criteria, 21 were mild, 35 were moderate, and 35 were severe. There was a significant positive relationship between TBI severity and MPAI-4 score on admission (χ = 12.77, df = 2, p = 0.0017).Median age was 27 years, and median duration of admission was 63 days. Employment and independent living status were available for 79 patients at 4 months. Seventy-three patients (92%) were in community-based employment, with 64 (81%) employed in a competitive or transitional work; 6 (8%) were unemployed or in sheltered work. Sixty-nine (87%) were living independently, and 10 (13%) were living with support in their own home, with no one requiring institutional care.Complete MPAI-4 scores were available for 79 patients. There were statistically and clinically significant improvements in MPAI-4 scores between admission and discharge for the overall group: median admission T score was 40.0 (95% confidence interval, 36.0-42.0) and on discharge was 31.0 (95% confidence interval, 27.0-36.0), a nine-point change (Z = 6.53, p < 0.0001). These improvements with rehabilitation were sustained when patients were subdivided by TBI severity or MPAI-4 limitations. CONCLUSION This study demonstrates significant functional improvements in military TBI patients following intensive inpatient multidisciplinary rehabilitation, which includes substantial vocational rehabilitation. At 4 months, 92% were employed, and 87% were living independently. LEVEL OF EVIDENCE Therapeutic study, level V; prognostic/epidemiologic study, level IV.

Published
2015

41. Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates

Author

Mark R. Johnson, Suren R. Sooranna, Cliff A. Astley, James W. MacDonald, Lakshmi Rajagopal, Roger C. Young, Aarthi R. Mohan, Theodor K. Bammler, Kristina M. Adams Waldorf, Lisa Ngo, Keith W. Vogel, Jesse Tsai, Audrey Baldessari, Bronwen R. Herbert, Ananya Das, Natasha Singh, Aasthaa Bansal, Louis Paolella, G. Michael Gough, and Michael G. Gravett

Subjects
Amniotic fluid, Preterm labor, Prostaglandin E2, Monocyte chemotactic protein 1, Uterus, uterine stretch, Dinoprost, Chemokine (C-C motif) ligand 2, Aminotic-fluid, chemistry.chemical_compound, Uterine stress, Pregnancy, Gene-expression, Rat myometrium, Amniocyte, Amnion, biology, Smooth-muscle-cells, Myometrium, Obstetrics & Gynecology, Obstetrics and Gynecology, Pigtail macaque, medicine.anatomical_structure, Models, Animal, Spiral arteries, Cytokines, Female, medicine.symptom, Macaca nemestrina, Pregnancy, Multiple, Life Sciences & Biomedicine, Mechanical stretch, Polyhydramnios, Choriodecidua, medicine.medical_specialty, Tumor necrosis factor, Shear-stress, Prostaglandin, Inflammation, Dinoprostone, Article, Prostaglandin F2 alpha, Andrology, Obstetric Labor, Premature, Internal medicine, medicine, Animals, Humans, RNA, Messenger, Obstetrics & Reproductive Medicine, Rhesus-monkeys, Science & Technology, business.industry, Interleukin-8, biology.organism_classification, medicine.disease, Endocrinology, chemistry, Paediatrics And Reproductive Medicine, Stress, Mechanical, business, Physiological transformation, Interleukin-1
Abstract

Objective Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model. Study Design A nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace. Results Preterm labor occurred in 3 of 6 animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an “inflammatory pulse” that correlated with preterm labor (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1β, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios and twins are involved in tissue remodeling and muscle growth. Conclusion Uterine overdistention by inflation of an intraamniotic balloon is associated with an inflammatory pulse that precedes and correlates with preterm labor. Our results indicate that inflammation is an early event after a mechanical stress on the uterus and leads to preterm labor when the stress is sufficiently great. Further, we find evidence of uterine tissue remodeling and muscle growth as a common, perhaps compensatory, response to uterine distension.

Published
2015

42. Preclinical safety and efficacy studies with an affinity-enhanced epithelial junction opener and PEGylated liposomal doxorubicin

Author

Chloe Zubieta, Michael Gough, Hongjie Wang, Roma Yumul, Nicole Urban, André Lieber, Martin Ho, Darrick Carter, Steve R. Roffler, Pascal Fender, Charles W. Drescher, Audrey Baldessari, Maximilian Richter, Drew May, Kamola Saydaminova, Division of Medical Genetics [Seattle], University of Washington [Seattle], Washington National Primate Research Center [Seattle], Institut Laue-Langevin (ILL), ILL, Laboratoire de physiologie cellulaire végétale (LPCV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physiologie Cellulaire and Végétale - UMR5168, Centre National de la Recherche Scientifique (CNRS), Health and Safety Executive, Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), European Synchroton Radiation Facility [Grenoble] (ESRF), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
lcsh:QH426-470, medicine.drug_class, Pharmacology, Monoclonal antibody, Cell junction, Article, Pegylated Liposomal Doxorubicin, law.invention, 03 medical and health sciences, 0302 clinical medicine, Therapeutic index, law, Genetics, Medicine, Mouse tumor, lcsh:QH573-671, Molecular Biology, 030304 developmental biology, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], business.industry, lcsh:Cytology, medicine.disease, 3. Good health, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], lcsh:Genetics, 030220 oncology & carcinogenesis, Toxicity, Recombinant DNA, Molecular Medicine, business, Ovarian cancer
Abstract

International audience; A central treatment resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. We have developed a small recombinant protein (JO-1) that triggers the transient opening of intercellular junctions and thus increases the efficacy of monoclonal antibodies and chemotherapeutic drugs without causing toxicity in mouse tumor models. Here, we provide data toward the clinical translation of an affinity-enhanced version of JO-1, which we call JO-4, in combination with PEGylated liposomal doxorubicin (PLD)/Doxil for ovarian cancer therapy. We have presented X-ray crystallography data suggesting a structural basis for the higher affinity of JO-4 to DSG2. We also confirmed JO-4 efficacy in a xenograft model with primary ovarian cancer cells showing that JO-4 can salvage Doxil therapy when given at a dose that was threefold lower than the therapeutic dose. Furthermore, we tested the safety of intravenous JO-4 alone and in combination with Doxil in Macaca fascicularis, an adequate animal model for predicting toxicity in humans. Our studies did not show critical JO-4-related toxicity or an increase of Doxil-related side effects. Our efficacy and safety data will help to support an Investigational new drug-filing for a JO-4/Doxil combination treatment.

Published
2015

43. Indicators of Recurrent Hospitalization for Pneumonia in the Elderly

Author

Michael Gough, Omar Bashir, Ali A. El Solh, Mifue Okada, and Thomas Brewer

Subjects
medicine.medical_specialty, Proportional hazards model, business.industry, Pneumonia severity index, Hazard ratio, medicine.disease, Comorbidity, Confidence interval, Pneumonia, Swallowing, Interquartile range, Internal medicine, medicine, Geriatrics and Gerontology, Intensive care medicine, business
Abstract

Objectives: To identify modifiable risk factors of late unplanned readmissions for elderly with community-acquired pneumonia. Design: A case-control study. Setting: Three university-affiliated tertiary-care hospitals. Participants: Two hundred four case-control pairs. Case patients referred to all patients readmitted with pneumonia 30 days to 1 year after discharge. Control subjects were matched for age, admission date, and residence before admission. Measurements: Baseline sociodemographic information, clinical data, activity of daily living (ADLs) information, and Charlson Comorbidity Index score were obtained. The Pneumonia Severity Index was calculated with swallowing dysfunction and pattern and extent of radiographic abnormalities, antimicrobial coverage, and total duration recorded. Results: Median time to readmission was 123 days (interquartile range=65–238 days). Readmission was not associated with increased severity or length of hospital stay. In a Cox proportional hazards regression model, swallowing dysfunction (hazard ratio (HR)=2.15, 95% confidence interval (CI)=1.46–2.97), current smoking (HR=2.04, 95% CI=1.48–2.82), use of tranquilizers (HR=1.5, 95% CI=1.02–2.22), and lower ADL scores (HR=1.06, 95% CI=1.02–1.10) were independently associated with readmission for pneumonia. The receipt of angiotensin-converting enzyme inhibitors (HR=0.46, 95% CI=0.27–0.78) and prior pneumococcal vaccination (HR=0.59, 95% CI=0.42–0.82) had a protective effect. Conclusion: Although there are limited effective measures to improve functional status, preventive strategies that include smoking cessation and pneumococcal vaccination should be actively pursued. Routine evaluation of swallowing dysfunction and use of pharmacological agents to improve the cough reflex deserve further evaluation in multicenter controlled trials.

Published
2004

44. Greater Sensitivity of Pigtailed Macaques (Macaca nemestrina) than Baboons to Total Body Irradiation

Author

Michael Gough, Stephen T. Kelley, Hans-Peter Kiem, Helle Bielefeldt-Ohmann, M. Durning, and H.D. Liggitt

Subjects
medicine.medical_specialty, Colon, Physiology, Biology, Kidney, medicine.disease_cause, Radiation Tolerance, Pathology and Forensic Medicine, Autologous stem-cell transplantation, medicine, Animals, Humans, Colitis, Adverse effect, Nephritis, General Veterinary, Graft Survival, Dose-Response Relationship, Radiation, Cytomegalovirus, Total body irradiation, medicine.disease, Surgery, Haematopoiesis, medicine.anatomical_structure, Cytomegalovirus Infections, Blood Vessels, Macaca nemestrina, Whole-Body Irradiation, Papio, Stem Cell Transplantation
Abstract

Two juvenile pigtailed macaques (animals 1 and 2) received total body irradiation (TBI) followed by autologous stem cell transplantation, by a procedure known to be well tolerated by baboons. In this procedure, the TBI consisted of treatment on two consecutive days with 255 cGy on one side, followed after 1–2 min by a similar dose on the other side. The two pigtailed macaques showed rapid haematopoietic engraftment, but succumbed either to systemic cytomegalovirus (CMV) infection and necrotising colitis or to haemorrhagic cystitis and tubulointerstitial nephritis. For four further pigtailed macaques (animals 3–6) the radiation procedure was changed to four equal doses of 255 cGy, given 6–12 h apart. Animals 4–6 all showed engraftment and survived for long periods (>218 days), with no, or only minor treatable, complications. Animal 3 failed to show engraftment and succumbed to radiation-induced vascular lesions and severe multiorgan haemorrhages. The results suggest that pigtailed macaques have a lower tolerance threshold than baboons, rhesus macaques or human beings to TBI, the adverse effects of TBI being indistinguishable from those seen in human patients. The results also suggest that a hyperfractionated radiation procedure can prevent radiation-induced morbidity and mortality in pigtailed macaques.

Published
2004

45. The Pulitzer Air Races : American Aviation and Speed Supremacy, 1920-1925

Author

Michael Gough and Michael Gough

Subjects
Aeronautics--Competitions, Airplane racing--History, Airplane racing--Awards
Abstract

Three years after American raceplanes failed dismally in the most important air race of 1920, a French magazine lamented that American'pilots have broken the records which we, here in France, considered as our own for so long.'The Pulitzer Trophy Air Races (1920 through 1925), endowed by the sons of publisher Joseph Pulitzer in his memory, brought about this remarkable turnaround. Pulitzer winning speeds increased from 157 to 249 mph, and Pulitzer racers, mounted on floats, twice won the most prestigious international air race--the Schneider Trophy Race for seaplanes. Airplanes, engines, propellers, and other equipment developed for the Pulitzers were sold domestically and internationally. More than a million spectators saw the Pulitzers; millions more read about them and watched them in newsreels. This, the first book about the Pulitzers, tells the story of businessmen, generals and admirals who saw racing as a way to drive aviation progress, designers and manufacturers who produced record-breaking racers, and dashing pilots who gave the races their public face. It emphasizes the roles played by the communities that hosted the races--Garden City (Long Island), Omaha, Detroit and Mt. Clemens, Michigan, St. Louis, and Dayton. The book concludes with an analysis of the Pulitzers'importance and why they have languished in obscurity for so long.

Published
2013

46. Dioxin, Agent Orange : The Facts

Author

Michael Gough and Michael Gough

Subjects
Pollution, Dioxins--Environmental aspects, Dioxins--Toxicology
Published
2013

47. Interleukin-7 improves CD4 T-cell reconstitution after autologous CD34 cell transplantation in monkeys

Author

Hailing Lu, Robert C. Hackman, Julia C. Morris, Jan Storek, Michael Gough, George E. Sale, Monja A. Dawson, Robert G. Andrews, Thurman Gillespy, Hans-Peter Kiem, David G. Maloney, Ansamma Joseph, and Peter A. Horn

Subjects
CD4-Positive T-Lymphocytes, Hemolytic anemia, medicine.medical_specialty, Filgrastim, medicine.medical_treatment, Immunology, Antigens, CD34, Neutropenia, Biology, Placebo, Polymerase Chain Reaction, Transplantation, Autologous, Biochemistry, Gastroenterology, Major Histocompatibility Complex, Internal medicine, Granulocyte Colony-Stimulating Factor, medicine, Animals, Autologous transplantation, DNA Primers, Stem Cell Factor, Base Sequence, Interleukin-7, Immunosuppression, Cell Biology, Hematology, Total body irradiation, Hematopoietic Stem Cells, medicine.disease, Recombinant Proteins, Transplantation, Papio, Stem Cell Transplantation, medicine.drug
Abstract

In mice, interleukin-7 (IL-7) hastens T-cell reconstitution and might cause autoimmune diseases, lymphoma, and osteoporosis. We assessed the effect of IL-7 on T-cell reconstitution and toxicity in baboons that underwent total body irradiation followed by autologous transplantation of marrow CD34 cells. Three baboons received placebo and 3 baboons received recombinant human IL-7 (rhIL-7, 75 μg/kg twice a day subcutaneously) between 6 and 10 weeks after transplantation. The mean increase in blood absolute CD4 T-cell counts was 0.9-fold in the placebo-treated animals versus 9.0-fold in those treated with IL-7 (P = .02). The increase observed in the IL-7–treated animals appeared attributable to peripheral expansion rather than de novo generation. The IL-7–treated animals had greater mean increases in the volumes of the spleen (2.0-fold with placebo versus 4.5-fold with IL-7, P = .02) and lymph nodes (1.8-fold with placebo versus 4.1-fold with IL-7,P = .10) but not the thymus (3.4-fold with placebo versus 1.1-fold with IL-7, P = .18). Side effects of IL-7 included thrombocytopenia and possibly neutropenia and hemolytic anemia. One IL-7–treated animal failed to thrive due to a disease resembling graft-versus-host disease. No animals developed lymphoma. Bone density was not decreased. In conclusion, IL-7 raises CD4 T-cell counts in irradiated primates. It remains to be determined whether this is associated with clinical benefit.

Published
2003

48. Antagonism—No Synergism—in Pairwise Tests of Carcinogens in Rats

Author

Michael Gough

Subjects
Male, Chemical compound, Carcinogenicity Tests, Pharmacology, Toxicology, chemistry.chemical_compound, Neoplasms, Good evidence, Animals, Carcinogenicity Test, Drug Antagonism, Carcinogen, Dose-Response Relationship, Drug, Chemistry, General Medicine, Rats, Inbred F344, United States, Rats, Drug Combinations, Dose–response relationship, National Institutes of Health (U.S.), Toxicity, Carcinogens, Female, Antagonism
Abstract

In the mid-1970s, the National Cancer Institute issued a contract for the testing of a dozen chemicals, most of them known to be carcinogenic in animals, in pairwise combinations. Those tests, which involved 918 pairwise tests and over 14,500 laboratory rats, produced no good evidence for any synergistic interactions in which exposure to two chemicals resulted in a number of tumors greater than the number produced by exposure to either chemical alone. A number of tests resulted in antagonism, in which the number of tumors in animals exposed to a pair of carcinogens was less than the number seen after exposure to either carcinogen by itself. More generally, the results indicate that synergism is an unlikely consequence when animals are exposed to pairs of chemicals, even when both chemicals are carcinogens.

Published
2002

49. Tumor antigen–specific induction of transcriptionally targeted retroviral vectors from chimeric immune receptor–modified T cells

Author

John, Chester, Anja, Ruchatz, Michael, Gough, Marka, Crittenden, Heung, Chong, François-Loïc, Cosset, François, Loïc-Cosset, Rosa Maria, Diaz, Kevin, Harrington, Luis, Alvarez-Vallina, and Richard, Vile

Subjects
Time Factors, Transcription, Genetic, T-Lymphocytes, Genetic enhancement, Genetic Vectors, Green Fluorescent Proteins, Biomedical Engineering, Mice, Nude, Bioengineering, Immune receptor, Biology, Polymerase Chain Reaction, Applied Microbiology and Biotechnology, Jurkat cells, Adenoviridae, Viral vector, Jurkat Cells, Mice, Immune system, Cell Adhesion, Tumor Cells, Cultured, Animals, Humans, Vector (molecular biology), Models, Genetic, T-cell receptor, Genetic Therapy, Flow Cytometry, Virology, Tumor antigen, Protein Structure, Tertiary, Luminescent Proteins, Retroviridae, Cancer research, Molecular Medicine, Biotechnology
Abstract

High-level systemic delivery of viral vectors to tumors has proved problematic as a result of immune neutralization, nonspecific adhesion, and clearance of circulating viral particles. Some cell types localize to tumors in response to particular biological properties associated with tumor growth. Their use to deliver viral vectors to tumors would allow precious viral stocks to be protected until they can be released at high local concentrations. Here, we describe a mechanism by which retroviral vector production by T cells can be regulated by a tumor-specific trigger through engagement of a chimeric immune receptor (CIR) with its target antigen. The virus that is released from the T cells can also be transcriptionally targeted. Finally, we show that it is possible to use vector-loaded, antigen-triggered human T cells as therapeutic, tumor-specific vector delivery cells in models of both local intratumoral and systemic delivery to both lung and liver metastases. This strategy incorporates multiple levels of targeting into the delivery system at the stages of surface targeting, viral production, and gene expression.

Published
2002

50. 0059 Health Education Yorkshire And The Humber (heyh) Surgical Simulation Collaborative

Author

Michael Gough, Daniel Glassman, James S. Tomlinson, Polly Dickerson, and Marina Yiasemidou

Subjects
Medical education, business.industry, media_common.quotation_subject, education, Plan (drawing), Simulation training, Health promotion, Nursing, Executive power, Medicine, Health education, Quality (business), Surgical simulation, business, Clinical skills, media_common
Abstract

Background For the past two years HEYH have run a successful, quality assured simulation programme, including non-technical skills, for core surgical trainees and general surgery St3 trainees.1 The latter will include ST4–6 trainees this year. ST3-ST6. Similarly, trauma and orthopaedics, paediatric surgery and ophthalmology are developing similar programmes. A number of issues must be addressed for successful implementation: out-of-hours access to skills centres, selection of suitable simulation models, faculty training, cost. Aim To develop a consortium of simulation fellows and programme directors that will assess existing resources, creates new simulation training opportunities and proposes a strategy for surgical simulation in the region. Results Simulation fellows from various surgical specialties have founded the Collaborative. To date we have identified problems with out-of-hours access to simulation centres, identified differing attitudes to the uptake of training between specialties and held a workshop to promote regional collaboration. We also plan to explore greater use of cadaveric dissection in simulation following the availability of Thiel-preserved bodies. Finally, we have gained representation at the Clinical Skills Network and Clinical Skills executive committee meetings. The collaborative hopes to promote a Surgical Consortium for Creating an Evolving Simulation Strategy (SuCCESS). This will require the support of HEYH which has the executive power to promote and implement change and the active involvement of the surgical training programme directors. Conclusion The SuCCESS initiative will aim to co-ordinate and enhance efforts for integration of simulation into surgical training. It will act as a source of support to surgical simulation projects and will be enriched by future simulation fellows employed in the region. Reference Clinical Skills and Simulation Strategy. http://yh.hee.nhs.uk/wp-content/uploads/sites/488/2013/06/Refreshed-Clinical-Skills-strategy-2014-2018.pdf

Published
2014

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