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1. Differentially expressed transcript isoforms associate with resistance to tuberculin skin test and interferon gamma release assay conversion.

Author

Jason D Simmons, R Max Segnitz, Kimberly A Dill-McFarland, Catherine M Stein, Glenna J Peterson, Harriet Mayanja-Kizza, W Henry Boom, and Thomas R Hawn

Subjects
Medicine, Science
Abstract

BackgroundA mechanistic understanding of uncommon immune outcomes such as resistance to infection has led to the development of novel therapies. Using gene level analytic methods, we previously found distinct monocyte transcriptional responses associated with resistance to Mycobacterium tuberculosis (Mtb) infection defined as persistently negative tuberculin skin test (TST) and interferon gamma release assay (IGRA) reactivity among highly exposed contacts (RSTR phenotype).ObjectiveUsing transcript isoform analyses, we aimed to identify novel RSTR-associated genes hypothesizing that previous gene-level differential expression analysis obscures isoform-specific differences that contribute to phenotype.Materials and methodsMonocytes from 49 RSTR versus 52 subjects with latent Mtb infection (LTBI) were infected with M. tuberculosis (H37Rv) or left unstimulated (media) prior to RNA isolation and sequencing. RSTR-associated gene expression was then identified using differential transcript isoform analysis.ResultsWe identified 81 differentially expressed transcripts (DETs) in 70 genes (FDR Conclusion and limitationsTranscript isoform-specific analyses identify transcriptional associations, such as those associated with resistance to TST/IGRA conversion, that are obscured when using gene-level approaches. These findings should be validated with additional RSTR cohorts and whether the newly identified candidate resistance genes directly influence the monocyte Mtb response requires functional study.

Published
2023
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2. Systemic lupus erythematosus and neutropaenia: a hallmark of haematological manifestations

Author

Laurent Arnaud, Zahir Amoura, Thierry Martin, Anne-Sophie Korganow, Aurélien Guffroy, Jean Sibilia, François Maurier, Bernard Bonnotte, Andreas Schwarting, Gilles Blaison, Pierre Kieffer, Nadine Magy-Bertrand, J Sibilia, Yannick Dieudonne, C Fiehn, M Rizzi, R Voll, Z Amoura, C Sordet, M Bartsch, A Schwarting, L Arnaud, Christoph Fiehn, JE Gottenberg, R Max, H-H Peter, J-L Pasquali, T Martín, A Meyer, J Thiel, P Kieffer, N Venhoff, H Lorenz, F Maurier, Aurore Meyer, Hannes Martin Lorenz, Jean-Louis Pennaforte, Hans-Hartmut Peter, Reinhard Edmund Voll, G Blaison, B Bonnotte, E Chatelus, E Ciobanu, F Duchene, JP Faller, A Gorse, O Hinschberger, F Jaeger, M Kilifa, N Magy-Bertrand, L Martzolff, J-L Pennaforte, V Poindron, S Revuz, M Samson, A Theulin, D Wahl, JC Weber, N Bartholomä, S Finzel, A Funkert, and M Hausberg

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Objective Systemic lupus is a chronic autoimmune disease characterised by its phenotypic heterogeneity. Neutropaenia is a frequent event in SLE occurring in 20%–40% of patients depending on the threshold value of neutrophil count. On a daily basis, the management of neutropaenia in SLE is difficult with several possible causes. Moreover, the infectious consequences of neutropaenia in SLE remain not well defined.Methods 998 patients from the Lupus BioBank of the upper Rhein (LBBR), a large German and French cohort of patients with SLE, mostly of Caucasian origin (83%), were included in this study. Neutropaenia was considered when neutrophil count was below 1800×106/L. An additional analysis of detailed medical records was done for 65 LBBR patients with neutropaenia.Results 208 patients with neutropaenia (21%) were compared with 779 SLE patients without neutropaenia. Neutropaenia in SLE was significantly associated with thrombocytopaenia (OR 4.11 (2.57–10.3)), lymphopaenia (OR 4.41 (2.51–11.5)) and low C3 (OR 1.91 (1.03–4.37)) in multivariate analysis. 65 representative patients with neutropaenia were analysed. Neutropaenia was moderate to severe in 38%, chronic in 31%, and both severe and chronic in 23% of cases. Moderate to severe and chronic neutropaenia were both associated with lymphopaenia and thrombopaenia. Chronic neutropaenia was also associated anti-Ro/SSA antibodies and moderate to severe neutropaenia with oral ulcers.Conclusion This study is to date the largest cohort to describe neutropaenia in SLE. Neutropaenia displays a strong association with other cytopaenias, suggesting a common mechanism. Chronic neutropaenia is associated with anti-Ro/SSA antibodies with or without identified Sjögren’s disease.

Published
2020
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4. The intrinsic substrate specificity of the human tyrosine kinome

Author

Yaron-Barir, Tomer M., Joughin, Brian A., Huntsman, Emily M., Kerelsky, Alexander, Cizin, Daniel M., Cohen, Benjamin M., Regev, Amit, Song, Junho, Vasan, Neil, Lin, Ting-Yu, Orozco, Jose M., Schoenherr, Christina, Sagum, Cari, Bedford, Mark T., Wynn, R. Max, Tso, Shih-Chia, Chuang, David T., Li, Lei, Li, Shawn S.-C., Creixell, Pau, Krismer, Konstantin, Takegami, Mina, Lee, Harin, Zhang, Bin, Lu, Jingyi, Cossentino, Ian, Landry, Sean D., Uduman, Mohamed, Blenis, John, Elemento, Olivier, Frame, Margaret C., Hornbeck, Peter V., Cantley, Lewis C., Turk, Benjamin E., Yaffe, Michael B., and Johnson, Jared L.

Published
2024
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5. Environmental and Social Change Drive the Explosive Emergence of Zika Virus in the Americas.

Author

Sofia Ali, Olivia Gugliemini, Serena Harber, Alexandra Harrison, Lauren Houle, Javarcia Ivory, Sierra Kersten, Rebia Khan, Jenny Kim, Chris LeBoa, Emery Nez-Whitfield, Jamieson O'Marr, Emma Rothenberg, R Max Segnitz, Stephanie Sila, Anna Verwillow, Miranda Vogt, Adrienne Yang, and Erin A Mordecai

Subjects
Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract

Since Zika virus (ZIKV) was detected in Brazil in 2015, it has spread explosively across the Americas and has been linked to increased incidence of microcephaly and Guillain-Barré syndrome (GBS). In one year, it has infected over 500,000 people (suspected and confirmed cases) in 40 countries and territories in the Americas. Along with recent epidemics of dengue (DENV) and chikungunya virus (CHIKV), which are also transmitted by Aedes aegypti and Ae. albopictus mosquitoes, the emergence of ZIKV suggests an ongoing intensification of environmental and social factors that have given rise to a new regime of arbovirus transmission. Here, we review hypotheses and preliminary evidence for the environmental and social changes that have fueled the ZIKV epidemic. Potential drivers include climate variation, land use change, poverty, and human movement. Beyond the direct impact of microcephaly and GBS, the ZIKV epidemic will likely have social ramifications for women's health and economic consequences for tourism and beyond.

Published
2017
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6. The Fight Tumour Blindness Registry: Efficient capture of high-quality real-world data in uveal melanoma

Author

O'Day, Roderick F., Conway, R. Max, Lim, Li-Anne, Giblin, Michael, Cherepanoff, Svetlana, Joshua, Anthony, McKay, Daniel, McKenzie, John D., Fog, Lotte S., Holly, Peta, Shackleton, Mark, Kee, Damien, Philips, Claire, McKelvie, Penny, Bhikoo, Riyaz, Hadden, Peter, Negretti, Guy S., Sagoo, Mandeep S., Damato, Bertil E., Sia, David, McGrath, Lindsay, Glasson, William, Isaacs, Timothy, Gillies, Mark, and Barthelmes, Daniel

Published
2024
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12. Effects of combination treatment with tezepelumab and allergen immunotherapy on nasal responses to allergen: A randomized controlled trial

Author

Corren, Jonathan, Larson, David, Altman, Matthew C., Segnitz, R. Max, Avila, Pedro C., Greenberger, Paul A., Baroody, Fuad, Moss, Mark H., Nelson, Harold, Burbank, Allison J., Hernandez, Michelle L., Peden, David, Saini, Sarbjit, Tilles, Stephen, Hussain, Iftikhar, Whitehouse, Don, Qin, Tielin, Villarreal, Miguel, Sever, Michelle, Wheatley, Lisa M., Nepom, Gerald T., and Sanda, Srinath

Published
2023
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14. Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial

Author

Jackson, Daniel J, Bacharier, Leonard B, Gergen, Peter J, Gagalis, Lisa, Calatroni, Agustin, Wellford, Stephanie, Gill, Michelle A, Stokes, Jeffrey, Liu, Andrew H, Gruchalla, Rebecca S, Cohen, Robyn T, Makhija, Melanie, Khurana Hershey, Gurjit K, O'Connor, George T, Pongracic, Jacqueline A, Sherenian, Michael G, Rivera-Spoljaric, Katherine, Zoratti, Edward M, Teach, Stephen J, Kattan, Meyer, Dutmer, Cullen M, Kim, Haejin, Lamm, Carin, Sheehan, William J, Segnitz, R Max, Dill-McFarland, Kimberly A, Visness, Cynthia M, Becker, Patrice M, Gern, James E, Sorkness, Christine A, Busse, William W, and Altman, Matthew C

Published
2022
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22. The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase

Author

White, Phillip J., McGarrah, Robert W., Grimsrud, Paul A., Tso, Shih-Chia, Yang, Wen-Hsuan, Haldeman, Jonathan M., Grenier-Larouche, Thomas, An, Jie, Lapworth, Amanda L., Astapova, Inna, Hannou, Sarah A., George, Tabitha, Arlotto, Michelle, Olson, Lyra B., Lai, Michelle, Zhang, Guo-Fang, Ilkayeva, Olga, Herman, Mark A., Wynn, R. Max, Chuang, David T., and Newgard, Christopher B.

Published
2018
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28. Therapeutic Effect of Targeting Branched‐Chain Amino Acid Catabolic Flux in Pressure‐Overload Induced Heart Failure

Author

Mengping Chen, Chen Gao, Jiayu Yu, Shuxun Ren, Menglong Wang, R. Max Wynn, David T. Chuang, Yibin Wang, and Haipeng Sun

Subjects
amino acids, heart failure, hypertrophy/remodeling, metabolism, therapy, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background Branched‐chain amino acid (BCAA) catabolic defect is an emerging metabolic hallmark in failing hearts in human and animal models. The therapeutic impact of targeting BCAA catabolic flux under pathological conditions remains understudied. Methods and Results BT2 (3,6‐dichlorobenzo[b]thiophene‐2‐carboxylic acid), a small‐molecule inhibitor of branched‐chain ketoacid dehydrogenase kinase, was used to enhance BCAA catabolism. After 2 weeks of transaortic constriction, mice with significant cardiac dysfunctions were treated with vehicle or BT2. Serial echocardiograms showed continuing pathological deterioration in left ventricle of the vehicle‐treated mice, whereas the BT2‐treated mice showed significantly preserved cardiac function and structure. Moreover, BT2 treatment improved systolic contractility and diastolic mechanics. These therapeutic benefits appeared to be independent of impacts on left ventricle hypertrophy but associated with increased gene expression involved in fatty acid utilization. The BT2 administration showed no signs of apparent toxicity. Conclusions Our data provide the first proof‐of‐concept evidence for the therapeutic efficacy of restoring BCAA catabolic flux in hearts with preexisting dysfunctions. The BCAA catabolic pathway represents a novel and potentially efficacious target for treatment of heart failure.

Published
2019
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33. In Search of Project Management Principles.

Author

Shepherd, Miles, Blampied, Nigel, Buttrick, Robert, Jucan, George, Piney, Crispin (“Kik”), Stevens, Chris, Violette, Dave, and Wideman, R. Max

Subjects
PROJECT management, STANDARDS
Abstract

The objective of this article is to determine whether a set of project management principles can be identified to serve as a common framework for developers and publishers of project management standards and guides. Twenty-two project management standards and other consensus documents were reviewed, revealing a common understanding across the globe of the requirements for effective project management. Potential statements of principles were extracted and clustered into four categories. The validated principles identified in each category were rewritten in a prespecified, consistent form. The resulting set of 12 principles should serve as a common basis for future standards and guides. [ABSTRACT FROM AUTHOR]

Published
2023
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42. Differentially expressed transcript isoforms associate with resistance to tuberculin skin test and interferon gamma release assay conversion.

Author

Simmons, Jason D., Segnitz, R. Max, Dill-McFarland, Kimberly A., Stein, Catherine M., Peterson, Glenna J., Mayanja-Kizza, Harriet, Boom, W. Henry, and Hawn, Thomas R.

Subjects
*INTERFERON gamma release tests, *GENE expression, *TUBERCULIN test, *SKIN tests, *LATENT infection
Abstract

Background: A mechanistic understanding of uncommon immune outcomes such as resistance to infection has led to the development of novel therapies. Using gene level analytic methods, we previously found distinct monocyte transcriptional responses associated with resistance to Mycobacterium tuberculosis (Mtb) infection defined as persistently negative tuberculin skin test (TST) and interferon gamma release assay (IGRA) reactivity among highly exposed contacts (RSTR phenotype). Objective: Using transcript isoform analyses, we aimed to identify novel RSTR-associated genes hypothesizing that previous gene-level differential expression analysis obscures isoform-specific differences that contribute to phenotype. Materials and methods: Monocytes from 49 RSTR versus 52 subjects with latent Mtb infection (LTBI) were infected with M. tuberculosis (H37Rv) or left unstimulated (media) prior to RNA isolation and sequencing. RSTR-associated gene expression was then identified using differential transcript isoform analysis. Results: We identified 81 differentially expressed transcripts (DETs) in 70 genes (FDR <0.05) comparing RSTR and LTBI phenotypes with the majority (n = 79 DETs) identified under Mtb-stimulated conditions. Seventeen of these genes were previously identified with gene-level bulk RNAseq analyses including genes in the IFNγ response that had increased expression among LTBI subjects, findings consistent with a clinical phenotype based on IGRA reactivity. Among the subset of 23 genes with positive differential expression among Mtb-infected RSTR monocytes, 13 were not previously identified. These novel DET genes included PDE4A and ZEB2, which each had multiple DETs with higher expression among RSTR subjects, and ACSL4 and GAPDH that each had a single transcript isoform associated with RSTR. Conclusion and limitations: Transcript isoform-specific analyses identify transcriptional associations, such as those associated with resistance to TST/IGRA conversion, that are obscured when using gene-level approaches. These findings should be validated with additional RSTR cohorts and whether the newly identified candidate resistance genes directly influence the monocyte Mtb response requires functional study. [ABSTRACT FROM AUTHOR]

Published
2023
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47. Residential Aged Care Facilities During the COVID-19 Pandemic: A Staff Survey on Impact and Resources.

Author

Chróinín, Danielle Ní, Anthony, Allicia, Acosta, R. Max, Thambyaiyah, Deborah, Hasan, Nasrin, and Patil, Arvin

Subjects
HEALTH facility employees, RESEARCH, SOCIAL support, AFFECT (Psychology), ATTITUDES of medical personnel, WORK, FISHER exact test, COMMUNITY health services, ACTIVITIES of daily living, PSYCHOSOCIAL factors, EXPERIENTIAL learning, RESIDENTIAL care, QUESTIONNAIRES, DESCRIPTIVE statistics, CHI-squared test, HOSPITAL care of older people, WORKING hours, LOGISTIC regression analysis, PERSONAL protective equipment, STAY-at-home orders, PART-time employment, DATA analysis software, COVID-19 pandemic, ELDER care, PERSONNEL management
Abstract

The current study explored the impact of the coronavirus disease 2019 (COVID-19) pandemic on staff in residential aged care facilities (RACFs). A hardcopy, voluntary, anonymous survey was circulated to local RACFs (June–July 2020), exploring challenges, staffing effects, mood within RACFs, and staff perceptions of supports. Overall, 105 staff members responded, which were mainly nursing personnel (67.6%) and owners/managers (10.5%). Seventy percent believed they were equipped to handle patients with COVID-19. One quarter reported personal protective equipment shortages. Respondents reported pressures to accept patients with COVID-19 from hospitals and/or keep residents in the RACF. One third reported staff "calling in sick" related to COVID-19/quarantine. Common compensatory strategies included increasing part-time workers' hours. Reported mood was largely positive. Most (86.4%) respondents felt supported by general practitioner and local geriatric outreach services. Opportunities to best support RACF staff require further research and dialogue. [Journal of Gerontological Nursing, 49(3), 13–17.] [ABSTRACT FROM AUTHOR]

Published
2023
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