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2,630 results on '"Ambrose A"'

1. Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase‑6

Author

Van Horn, Kurt S, Wang, Dongju, Medina-Cleghorn, Daniel, Lee, Peter S, Bryant, Clifford, Altobelli, Chad, Jaishankar, Priyadarshini, Leung, Kevin K, Ng, Raymond A, Ambrose, Andrew J, Tang, Yinyan, Arkin, Michelle R, and Renslo, Adam R

Subjects
Rare Diseases, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Humans, Caspase 6, Cysteine, Caspases, Apoptosis, Cysteine Proteinase Inhibitors, Chemical Sciences, General Chemistry
Abstract

Caspases are a family of cysteine-dependent proteases with important cellular functions in inflammation and apoptosis, while also implicated in human diseases. Classical chemical tools to study caspase functions lack selectivity for specific caspase family members due to highly conserved active sites and catalytic machinery. To overcome this limitation, we targeted a non-catalytic cysteine residue (C264) unique to caspase-6 (C6), an enigmatic and understudied caspase isoform. Starting from disulfide ligands identified in a cysteine trapping screen, we used a structure-informed covalent ligand design to produce potent, irreversible inhibitors (3a) and chemoproteomic probes (13-t) of C6 that exhibit unprecedented selectivity over other caspase family members and high proteome selectivity. This approach and the new tools described will enable rigorous interrogation of the role of caspase-6 in developmental biology and in inflammatory and neurodegenerative diseases.

Published
2023

2. Walking for Cognitive Health: Previous Parity Moderates the Relationship Between Self-Reported Walking and Cognition.

Author

Barha, Cindy K, Best, John R, Rosano, Caterina, Yaffe, Kristine, Catov, Janet M, and Liu-Ambrose, Teresa

Subjects
Public Health, Health Sciences, Brain Disorders, Behavioral and Social Science, Basic Behavioral and Social Science, Aging, Clinical Research, Good Health and Well Being, Male, Pregnancy, Humans, Female, Aged, Parity, Self Report, Cognition, Cognitive Dysfunction, Walking, Cognitive aging, Physical activity, Reproductive experience, Clinical Sciences, Gerontology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundOlder females show greater cognitive gains from physical activity (PA) than males, which may be related to long-term consequences of female-specific reproductive events (eg, pregnancy) on cognitive health.MethodsTo determine whether previous parity could moderate the relationship between PA and cognitive decline in older women, we conducted secondary analyses of data from the Health, Aging, and Body Composition Study. We tested whether the association between average PA over 10 years and cognition (Modified Mini-Mental State Examination [3MS]) and executive functioning (digit symbol substitution test [DSST]) over 10 years varied by previous parity (nulliparity, low parity, medium parity, and grand multiparity). An analysis of covariance was performed with cognition (average and change over 10 years) as the dependent variables, parity as a categorical predictor, average PA as a continuous predictor, and a set of relevant covariates.ResultsSignificant interactions were found between PA and parity group for all 4 comparisons: average 3MS (p = .014), average DSST (p = .032), change in 3MS (p = .016), and change in DSST (p = .017). Simple slope analyses indicated the positive relationship between PA and average 3MS and DSST was only significant in the nulliparity and grand multiparity groups, and the positive relationship between PA and change in 3MS and DSST was only significant in the grand multiparity group.ConclusionThe findings suggest the relationship between self-reported walking and cognitive performance was strongest in the groups at risk for cognitive decline and dementia, the nulliparous and grand multiparous groups.

Published
2023

3. Deep analysis of CD4 T cells in the rhesus CNS during SIV infection

Author

Elizaldi, Sonny R, Verma, Anil, Ma, Zhong-Min, Ott, Sean, Rajasundaram, Dhivyaa, Hawes, Chase E, Lakshmanappa, Yashavanth Shaan, Cottrell, Mackenzie L, Kashuba, Angela DM, Ambrose, Zandrea, Lifson, Jeffrey D, Morrison, John H, and Iyer, Smita S

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, HIV/AIDS, Infectious Diseases, Sexually Transmitted Infections, Neurosciences, Infection, Good Health and Well Being, Animals, Humans, CD4-Positive T-Lymphocytes, Simian Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus, Macaca mulatta, Central Nervous System, HIV Infections, Viral Load, Simian immunodeficiency virus, Microbiology, Virology, Medical microbiology
Abstract

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)-known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART.

Published
2023

4. A guide to the BRAIN Initiative Cell Census Network data ecosystem

Author

Hawrylycz, Michael, Martone, Maryann E, Ascoli, Giorgio A, Bjaalie, Jan G, Dong, Hong-Wei, Ghosh, Satrajit S, Gillis, Jesse, Hertzano, Ronna, Haynor, David R, Hof, Patrick R, Kim, Yongsoo, Lein, Ed, Liu, Yufeng, Miller, Jeremy A, Mitra, Partha P, Mukamel, Eran, Ng, Lydia, Osumi-Sutherland, David, Peng, Hanchuan, Ray, Patrick L, Sanchez, Raymond, Regev, Aviv, Ropelewski, Alex, Scheuermann, Richard H, Tan, Shawn Zheng Kai, Thompson, Carol L, Tickle, Timothy, Tilgner, Hagen, Varghese, Merina, Wester, Brock, White, Owen, Zeng, Hongkui, Aevermann, Brian, Allemang, David, Ament, Seth, Athey, Thomas L, Baker, Cody, Baker, Katherine S, Baker, Pamela M, Bandrowski, Anita, Banerjee, Samik, Bishwakarma, Prajal, Carr, Ambrose, Chen, Min, Choudhury, Roni, Cool, Jonah, Creasy, Heather, D’Orazi, Florence, Degatano, Kylee, Dichter, Benjamin, Ding, Song-Lin, Dolbeare, Tim, Ecker, Joseph R, Fang, Rongxin, Fillion-Robin, Jean-Christophe, Fliss, Timothy P, Gee, James, Gillespie, Tom, Gouwens, Nathan, Zhang, Guo-Qiang, Halchenko, Yaroslav O, Harris, Nomi L, Herb, Brian R, Hintiryan, Houri, Hood, Gregory, Horvath, Sam, Huo, Bingxing, Jarecka, Dorota, Jiang, Shengdian, Khajouei, Farzaneh, Kiernan, Elizabeth A, Kir, Huseyin, Kruse, Lauren, Lee, Changkyu, Lelieveldt, Boudewijn, Li, Yang, Liu, Hanqing, Liu, Lijuan, Markuhar, Anup, Mathews, James, Mathews, Kaylee L, Mezias, Chris, Miller, Michael I, Mollenkopf, Tyler, Mufti, Shoaib, Mungall, Christopher J, Orvis, Joshua, Puchades, Maja A, Qu, Lei, Receveur, Joseph P, Ren, Bing, Sjoquist, Nathan, Staats, Brian, Tward, Daniel, van Velthoven, Cindy TJ, Wang, Quanxin, Xie, Fangming, Xu, Hua, Yao, Zizhen, and Yun, Zhixi

Subjects
Biological Sciences, Genetics, Neurosciences, Data Science, Mental Health, 1.1 Normal biological development and functioning, Neurological, Animals, Humans, Mice, Brain, Ecosystem, Neurons, Agricultural and Veterinary Sciences, Medical and Health Sciences, Developmental Biology, Agricultural, veterinary and food sciences, Biological sciences, Biomedical and clinical sciences
Abstract

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed by the BICCN, and to accessing and using these data and extensive resources, including the BRAIN Cell Data Center (BCDC), which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted toward Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain.

Published
2023

5. World guidelines for falls prevention and management for older adults: a global initiative

Author

Montero-Odasso, Manuel, van der Velde, Nathalie, Martin, Finbarr C, Petrovic, Mirko, Tan, Maw Pin, Ryg, Jesper, Aguilar-Navarro, Sara, Alexander, Neil B, Becker, Clemens, Blain, Hubert, Bourke, Robbie, Cameron, Ian D, Camicioli, Richard, Clemson, Lindy, Close, Jacqueline, Delbaere, Kim, Duan, Leilei, Duque, Gustavo, Dyer, Suzanne M, Freiberger, Ellen, Ganz, David A, Gómez, Fernando, Hausdorff, Jeffrey M, Hogan, David B, Hunter, Susan MW, Jauregui, Jose R, Kamkar, Nellie, Kenny, Rose-Anne, Lamb, Sarah E, Latham, Nancy K, Lipsitz, Lewis A, Liu-Ambrose, Teresa, Logan, Pip, Lord, Stephen R, Mallet, Louise, Marsh, David, Milisen, Koen, Moctezuma-Gallegos, Rogelio, Morris, Meg E, Nieuwboer, Alice, Perracini, Monica R, Pieruccini-Faria, Frederico, Pighills, Alison, Said, Catherine, Sejdic, Ervin, Sherrington, Catherine, Skelton, Dawn A, Dsouza, Sabestina, Speechley, Mark, Stark, Susan, Todd, Chris, Troen, Bruce R, van der Cammen, Tischa, Verghese, Joe, Vlaeyen, Ellen, Watt, Jennifer A, Masud, Tahir, Singh, Devinder Kaur Ajit, Aguilar-Navarro, Sara G, Caona, Edgar Aguilera, Allen, Natalie, Anweiller, Cedric, Avila-Funes, Alberto, Santos, Renato Barbosa, Batchelor, Francis, Beauchamp, Marla, Birimoglu, Canan, Bohlke, Kayla, Bourke, Robert, Bouzòn, Christina Alonzo, Bridenbaugh, Stephanie, Buendia, Patricio Gabriel, Cameron, Ian, Canning, Colleen, Cano-Gutierrez, Carlos Alberto, Carbajal, Juan Carlos, de Abreu, Daniela Cristina Carvalho, Casas-Herrero, Alvaro, Ceriani, Alejandro, Cesari, Matteo, Chiari, Lorenzo, Alemǻn, Luis Manuel Cornejo, Dawson, Rik, Doody, Paul, Dyer, Suzanne, Ellmers, Toby, Fairhall, Nicola, Ferruci, Luigi, and Frith, James

Subjects
Biomedical and Clinical Sciences, Health Services and Systems, Public Health, Health Sciences, Clinical Sciences, Aging, Prevention, Clinical Research, Patient Safety, Physical Injury - Accidents and Adverse Effects, Health and social care services research, 8.1 Organisation and delivery of services, 7.1 Individual care needs, Management of diseases and conditions, Good Health and Well Being, Aged, Caregivers, Humans, Independent Living, Quality of Life, Risk Assessment, falls, injury, aged, guidelines, recommendations, clinical practice, world, global, consensus, older people, Task Force on Global Guidelines for Falls in Older Adults, Public Health and Health Services, Psychology, Geriatrics, Clinical sciences, Health services and systems, Applied and developmental psychology
Abstract

Backgroundfalls and fall-related injuries are common in older adults, have negative effects on functional independence and quality of life and are associated with increased morbidity, mortality and health related costs. Current guidelines are inconsistent, with no up-to-date, globally applicable ones present.Objectivesto create a set of evidence- and expert consensus-based falls prevention and management recommendations applicable to older adults for use by healthcare and other professionals that consider: (i) a person-centred approach that includes the perspectives of older adults with lived experience, caregivers and other stakeholders; (ii) gaps in previous guidelines; (iii) recent developments in e-health and (iv) implementation across locations with limited access to resources such as low- and middle-income countries.Methodsa steering committee and a worldwide multidisciplinary group of experts and stakeholders, including older adults, were assembled. Geriatrics and gerontological societies were represented. Using a modified Delphi process, recommendations from 11 topic-specific working groups (WGs), 10 ad-hoc WGs and a WG dealing with the perspectives of older adults were reviewed and refined. The final recommendations were determined by voting.Recommendationsall older adults should be advised on falls prevention and physical activity. Opportunistic case finding for falls risk is recommended for community-dwelling older adults. Those considered at high risk should be offered a comprehensive multifactorial falls risk assessment with a view to co-design and implement personalised multidomain interventions. Other recommendations cover details of assessment and intervention components and combinations, and recommendations for specific settings and populations.Conclusionsthe core set of recommendations provided will require flexible implementation strategies that consider both local context and resources.

Published
2022

6. Caspase‐6‐cleaved tau is relevant in Alzheimer's disease and marginal in four‐repeat tauopathies: Diagnostic and therapeutic implications

Author

Theofilas, Panos, Piergies, Antonia MH, Oh, Ian, Bin Lee, Yoo, Li, Song Hua, Pereira, Felipe L, Petersen, Cathrine, Ehrenberg, Alexander J, Eser, Rana A, Ambrose, Andrew J, Chin, Brian, Yang, Teddy, Khan, Shireen, Ng, Raymond, Spina, Salvatore, Seeley, Willian W, Miller, Bruce L, Arkin, Michelle R, and Grinberg, Lea T

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurodegenerative, Aging, Frontotemporal Dementia (FTD), Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Biotechnology, Alzheimer's Disease, Dementia, Alzheimer's Disease Related Dementias (ADRD), Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Brain, Caspase 6, Humans, Neurons, Tauopathies, tau Proteins, Alzheimer's disease, caspase-6, cell counting, immunohistochemistry, tau cleavage, tau hyperphosphorylation, tau isoforms, tauopathies, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

AimTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates tau fragments that may be toxic. Yet the relationship between aCasp-6, different forms of tr-tau and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer's disease (AD) and other tauopathies remains unclear.MethodsWe generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used five-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau and their co-occurrence in healthy controls, AD and primary tauopathies.ResultsCasp-6 activation was strongest in AD and Pick's disease (PiD) but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD and PiD than in 4R tauopathies and disproportionally higher when normalising by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr-tau positive neurons in AD and PiD lacked p-tau aggregates, a finding we confirmed using several p-tau antibodies.ConclusionsEarly modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD and PiD but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that many vulnerable neurons to tau pathology go undetected when using conventional p-tau antibodies. Therapeutic strategies against tr-tau pathology could be necessary to modulate the extent of tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD and PiD supports the development of biofluid biomarkers against tr-tau to detect AD and PiD and differentiate them from 4R tauopathies at a patient level.

Published
2022

7. Protocol for SYNchronising Exercises, Remedies in GaIt and Cognition at Home (SYNERGIC@Home): feasibility of a home-based double-blind randomised controlled trial to improve gait and cognition in individuals at risk for dementia

Author

McGibbon, Chris, Jarrett, Pam, Handrigan, Grant, Bouchard, Danielle, Tranchant, Carole C, Sexton, Andrew M, Yetman, Linda, Robinson, Bryn, Crapoulet, Stephanie, Chamard-Witkowski, Ludivine, Liu-Ambrose, Teresa, Middleton, Laura Elizabeth, Almeida, Quincy J, Bherer, Louis, Lim, Andrew, Speechley, Mark, Kamkar, Nellie, Odasso, Manuel Montero, Chertkow, Howard, Belleville, Sylvie, Feldman, Howard, Montero-Odasso, Manuel, Nygaard, Haakon, Alcock, Danielle, Anderson, Nicole, Banks, Sarah, Brewster, Paul, Chan, Senny, Cuesta, Marc, Das, Samir, Evans, Carol, Ferland, Guylaine, Herold, Tati, Hofer, Scott, Itzhak, Inbal, Jacobs, Diane, Lupo, Jody-Lynn, Madlensky, Lisa, Messer, Karen, Mohades, Zia, Revta, Carolyn, Robillard, Julie, Slack, Penny, Smith, Eric, Walker, Jennifer, and Zou, Jingjing

Subjects
Clinical Research, Aging, Acquired Cognitive Impairment, Alzheimer's Disease, Brain Disorders, Behavioral and Social Science, Neurodegenerative, Rehabilitation, Prevention, Neurosciences, Dementia, Mind and Body, Nutrition, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Sleep Research, Clinical Trials and Supportive Activities, 6.7 Physical, Evaluation of treatments and therapeutic interventions, Neurological, Good Health and Well Being, Aged, Alzheimer Disease, Cognition, Double-Blind Method, Exercise, Feasibility Studies, Gait, Humans, Randomized Controlled Trials as Topic, Canadian Consortium on Neurodegeneration in Aging (CCNA), CAN-THUMBS UP Group, GERIATRIC MEDICINE, Neuropathology, Physiology, Clinical Sciences, Public Health and Health Services, Other Medical and Health Sciences
Abstract

IntroductionPhysical exercise and cognitive training have the potential to enhance cognitive function and mobility in older adults at risk of Alzheimer's disease and related dementia (ADRD), but little is known about the feasibility of delivering multidomain interventions in home settings of older adults at risk of ADRD. This study aims to assess the feasibility of home-based delivery of exercise and cognitive interventions, and to evaluate the relationship between participants' intervention preferences and their subsequent adherence. Secondary objectives include the effect of the interventions on ADRD risk factors, including frailty, mobility, sleep, diet and psychological health.Methods and analysisThe SYNchronising Exercises, Remedies in GaIt and Cognition at Home (SYNERGIC@Home) feasibility trial is a randomised control trial that follows a 2×2 factorial design, with a 16-week home-based intervention programme (3 sessions per week) of physical exercises and cognitive training. Participants will be randomised in blocks of four to one of the following four arms: (1) combined exercise (aerobic and resistance)+cognitive training (NEUROPEAK); (2) combined exercise+control cognitive training (web searching); (3) control exercise (balance and toning)+cognitive training; and (4) control exercise+control cognitive training. SYNERGIC@Home will be implemented through video conferencing. Baseline and post-intervention assessments at 4-month and 10-month follow-up will include measures of cognition, frailty, mobility, sleep, diet and psychological health. Primary feasibility outcome is adherence to the interventions. Primary analytic outcome is the relationship between pre-allocation preference for a given intervention and subsequent adherence to the allocated intervention. A series of secondary analytic outcomes examining the potential effect of the individual and combined interventions on cognitive, mobility and general well-being will be measured at baseline and follow-up.Ethics and disseminationEthics approval was granted by the relevant research ethics boards. Findings of the study will be presented to stakeholders and published in peer-reviewed journals and at provincial, national and international conferences.Trial registration numberNCT04997681, Pre-results.

Published
2022

8. Resilience, Physical Activity, and Depression in Women Living With HIV in the San Francisco Bay Area: A Cross-sectional Study

Author

Ambrose, Patricia R, Cuca, Yvette P, Baguso, Glenda N, Hoffmann, Thomas J, and Dawson-Rose, Carol

Subjects
Public Health, Health Sciences, Depression, Clinical Research, HIV/AIDS, Behavioral and Social Science, Infectious Diseases, Mental Health, Prevention, Mental health, Good Health and Well Being, Cross-Sectional Studies, Exercise, Female, HIV Infections, Humans, Resilience, Psychological, San Francisco, depression, HIV, physical activity, resilience, women, Nursing
Abstract

AbstractThere is a lack of literature on the effects of physical activity and depression on resilience in women living with HIV. This cross-sectional study examined the associations of sociodemographic factors, physical activity, and depression on resilience among 97 women living with HIV using linear regression models. Among these women, the mean resilience score was 70.7 (SD 16.3), the majority were insufficiently active (67.0%), and 45.4% had a Patient Health Questionnaire-9 score that indicated at least moderate depression. In a multivariable analysis, depression was negatively associated with resilience, and education was positively associated with resilience (p < .0001; p = .031). There was no significant correlation between physical activity and depression or resilience. An exploratory analysis did not indicate that depression mediated the relationship between physical activity and resilience. There is a need to address low levels of physical activity in women living with HIV. Interventions that address resilience and depressive symptoms may lead to improved mental health.

Published
2022

9. Understanding the role of incentives for achieving and sustaining viral suppression: A qualitative sub-study of a financial incentives trial in Uganda

Author

Camlin, Carol S, Marson, Kara, Ndyabakira, Alex, Getahun, Monica, Emperador, Devy, Byamukama, Ambrose, Kwarisiima, Dalsone, Thirumurthy, Harsha, and Chamie, Gabriel

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Pediatric AIDS, HIV/AIDS, Clinical Research, Nutrition, Prevention, Mind and Body, Mental Health, Behavioral and Social Science, Clinical Trials and Supportive Activities, Health Services, Infectious Diseases, Pediatric, 7.1 Individual care needs, Management of diseases and conditions, Infection, Good Health and Well Being, Zero Hunger, HIV Infections, Humans, Medication Adherence, Motivation, Qualitative Research, Uganda, Viral Load, General Science & Technology
Abstract

BackgroundViral suppression among people living with HIV (PLHIV) is essential for protecting health and preventing HIV transmission, yet globally, rates of viral suppression are sub-optimal. Interventions to improve HIV prevention and care cascade outcomes remain vital. Financial incentives hold promise for improving these outcomes, yet to date, clinical trial results have been mixed.MethodsThis qualitative sub-study, embedded in a trial (NCT02890459) in Uganda to test whether incentives are effective for achieving viral suppression in PLHIV, sought to enhance our understanding of the factors that influence this outcome. Forty-nine (n = 49) PLHIV, purposely sampled to balance across gender, study arm, and viral suppression status, were interviewed to explore barriers and motivations for care engagement, adherence, and viral suppression, and attributions for decision-making, including perceived influence of incentives on behaviors.ResultsWhile many participants with undetectable viral load (VL) who received incentives said the incentives motivated their ART adherence, others expressed intrinsic motivation for adherence. All felt that incentives reduced burdens of transport costs, lost income due to time spent away from work, and food insecurity. Incentives may have activated attention and memory for some, as excitement about anticipating incentives helped them adhere to medication schedules. In comparison, participants who were randomized to receive incentives but had detectable VL faced a wider range, complexity and severity of challenges to care engagement. Notably, their narratives included more accounts of poor treatment in clinics, food insecurity, and severe forms of stigma. With or without incentives, adherence was reinforced through experiencing restored health due to ART, social support (especially from partners), and good quality counseling and clinical care.ConclusionsIn considering why incentives sometimes fail to achieve behavior change, it may be helpful to attend to the full set of factors- psychological, interpersonal, social and structural- that militate against the behavior change required to achieve behavioral outcomes. To be effective, incentives may need to be combined with other interventions to address the spectrum of barriers to care engagement.

Published
2022

10. Cryoablation for Palliation of Painful Bone Metastases: The MOTION Multicenter Study.

Author

Jennings, Jack, Prologo, J, Garnon, Julien, Gangi, Afshin, Buy, Xavier, Palussière, Jean, Kurup, A, Callstrom, Matthew, Genshaft, Scott, Abtin, Fereidoun, Huang, Ambrose, Iannuccilli, Jason, Pilleul, Frank, Mastier, Charles, Littrup, Peter, de Baère, Thierry, and Deschamps, Frédéric

Subjects
Ablation Techniques, Metastases, Pain Management, Radiation Therapy/Oncology, Adult, Bone Neoplasms, Cryosurgery, Humans, Male, Middle Aged, Pain, Prospective Studies, Quality of Life
Abstract

PURPOSE: To assess the clinical effectiveness of cryoablation for palliation of painful bone metastases. MATERIALS AND METHODS: MOTION (Multicenter Study of Cryoablation for Palliation of Painful Bone Metastases) (ClinicalTrials.gov NCT02511678) was a multicenter, prospective, single-arm study of adults with metastatic bone disease who were not candidates for or had not benefited from standard therapy, that took place from February 2016 to March 2018. At baseline, participants rated their pain using the Brief Pain Inventory-Short Form (reference range from 0 to 10 points); those with moderate to severe pain, who had at least one metastatic candidate tumor for ablation, were included. The primary effectiveness endpoint was change in pain score from baseline to week 8. Participants were followed for 24 weeks after treatment. Statistical analyses included descriptive statistics and logistic regression to evaluate changes in pain score over the postprocedure follow-up period. RESULTS: A total of 66 participants (mean age, 60.8 years ± 14.3 [standard deviation]; 35 [53.0%] men) were enrolled and received cryoablation; 65 completed follow-up. Mean change in pain score from baseline to week 8 was -2.61 points (95% CI: -3.45, -1.78). Mean pain scores improved by 2 points at week 1 and reached clinically meaningful levels (more than a 2-point decrease) after week 8; scores continued to improve throughout follow-up. Quality of life improved, opioid doses were stabilized, and functional status was maintained over 6 months. Serious adverse events occurred in three participants. CONCLUSION: Cryoablation of metastatic bone tumors provided rapid and durable pain palliation, improved quality of life, and offered an alternative to opioids for pain control.Keywords: Ablation Techniques, Metastases, Pain Management, Radiation Therapy/OncologySupplemental material is available for this article.© RSNA, 2021.

Published
2021

11. Peripartum management of a patient with catecholaminergic polymorphic ventricular tachycardia.

Author

Jimenez, Erick, McGill, Mark, Ambrose, Matthew, and Cortez, Daniel

Subjects
arrhythmia, beta-blockers, palpitations, pregnancy, ventricular tachycardia, Adult, Anesthesia, Epidural, Anesthesia, Obstetrical, Defibrillators, Implantable, Delivery, Obstetric, Electrocardiography, Female, Humans, Peripartum Period, Pregnancy, Tachycardia, Ventricular, Treatment Outcome
Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal cardiac channelopathy characterized by episodes of ventricular tachycardia (VT) during exercise or in stressful situations. As the peripartum period creates a stressful environment, we describe our approach of this rare condition in a very common situation, child birth.

Published
2021

12. University Stormwater Management within Urban Environmental Regulatory Regimes: Barriers to Progressivity or Opportunities to Innovate?

Author

Pierce, Gregory, Gmoser-Daskalakis, Kyra, Jessup, Kelsey, Grant, Stanley B, Mehring, Andrew, Winfrey, Brandon, Rippy, Megan A, Feldman, David, Holden, Patricia, Ambrose, Richard, and Levin, Lisa

Subjects
Environmental Management, Engineering, Environmental Sciences, Law and Legal Studies, Environmental Engineering, Clinical Research, Sustainable Cities and Communities, Cities, Humans, Rain, Universities, Environmental governance, Regulatory compliance, University campuses, Stormwater management, Ecology
Abstract

U.S. public university campuses are held directly responsible for compliance with many of the same federal- and state-level environmental regulations as cities, including stormwater management. While operating as 'cities within cities' in many respects, campuses face unique constraints in achieving stormwater regulatory compliance. To compare the abilities of campuses to comply with stormwater regulations to municipalities, we conduct mixed-methods research using primary data from five University of California (UC) campuses. Public universities constituted over 20% of California's "nontraditional" permittees under the municipal separate storm sewer system (MS4) regulation regime in 2013. We utilize semi-structured interviews with campus and regulatory officials, a survey of campus students and staff around support and willingness to pay for innovative stormwater management, and content analysis of campus stormwater management documents to examine challenges to public university stormwater compliance. We find that, despite their progressive environmental practices in other areas like energy and water conservation, even as compared to cities, stormwater management practices on the evaluated campuses are constrained by several factors: infrastructure financing limitations, lack of transparent and coordinated decision-making, a lack of campus resident involvement, and regulatory inflexibility. Our study provides new insights, both for understanding campuses as sustainable 'cities within cities' and more broadly for urban environmental compliance regimes globally.

Published
2021

13. Development and validation of risk prediction models for COVID-19 positivity in a hospital setting

Author

Ng, Ming-Yen, Wan, Eric Yuk Fai, Wong, Ho Yuen Frank, Leung, Siu Ting, Lee, Jonan Chun Yin, Chin, Thomas Wing-Yan, Lo, Christine Shing Yen, Lui, Macy Mei-Sze, Chan, Edward Hung Tat, Fong, Ambrose Ho-Tung, Fung, Sau Yung, Ching, On Hang, Chiu, Keith Wan-Hang, Chung, Tom Wai Hin, Vardhanbhuti, Varut, Lam, Hiu Yin Sonia, To, Kelvin Kai Wang, Chiu, Jeffrey Long Fung, Lam, Tina Poy Wing, Khong, Pek Lan, Liu, Raymond Wai To, Chan, Johnny Wai Man, Wu, Alan Ka Lun, Lung, Kwok-Cheung, Hung, Ivan Fan Ngai, Lau, Chak Sing, Kuo, Michael D, and Ip, Mary Sau-Man

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Area Under Curve, COVID-19, Female, Hospitals, Humans, Logistic Models, Male, Middle Aged, Nomograms, Probability, SARS-CoV-2, Chest x-ray, Nomogram, Prediction model, White cell count, Microbiology, Medical Microbiology, Public Health and Health Services, Clinical sciences, Epidemiology, Public health
Abstract

ObjectivesTo develop: (1) two validated risk prediction models for coronavirus disease-2019 (COVID-19) positivity using readily available parameters in a general hospital setting; (2) nomograms and probabilities to allow clinical utilisation.MethodsPatients with and without COVID-19 were included from 4 Hong Kong hospitals. The database was randomly split into 2:1: for model development database (n = 895) and validation database (n = 435). Multivariable logistic regression was utilised for model creation and validated with the Hosmer-Lemeshow (H-L) test and calibration plot. Nomograms and probabilities set at 0.1, 0.2, 0.4 and 0.6 were calculated to determine sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV).ResultsA total of 1330 patients (mean age 58.2 ± 24.5 years; 50.7% males; 296 COVID-19 positive) were recruited. The first prediction model developed had age, total white blood cell count, chest x-ray appearances and contact history as significant predictors (AUC = 0.911 [CI = 0.880-0.941]). The second model developed has the same variables except contact history (AUC = 0.880 [CI = 0.844-0.916]). Both were externally validated on the H-L test (p = 0.781 and 0.155, respectively) and calibration plot. Models were converted to nomograms. Lower probabilities give higher sensitivity and NPV; higher probabilities give higher specificity and PPV.ConclusionTwo simple-to-use validated nomograms were developed with excellent AUCs based on readily available parameters and can be considered for clinical utilisation.

Published
2020

14. The Stringent Response Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection Through the Purine Biosynthetic Pathway.

Author

Li, Liang, Bayer, Arnold S, Cheung, Ambrose, Lu, Lou, Abdelhady, Wessam, Donegan, Niles P, Hong, Jong-In, Yeaman, Michael R, and Xiong, Yan Q

Subjects
Infectious Diseases, Emerging Infectious Diseases, Vaccine Related, Biodefense, Antimicrobial Resistance, Prevention, Genetics, Aetiology, 2.1 Biological and endogenous factors, Infection, Animals, Anti-Bacterial Agents, Bacteremia, Biosynthetic Pathways, Disease Models, Animal, Endocarditis, Humans, Methicillin, Methicillin-Resistant Staphylococcus aureus, Purines, Rabbits, Staphylococcal Infections, MRSA, stringent response, (p)ppGpp, purine biosynthesis, persistence, endovascular infection, MRSA, Biological Sciences, Medical and Health Sciences, Microbiology
Abstract

Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections represent a significant clinical-therapeutic challenge. Of particular concern is antibiotic treatment failure in infections caused by MRSA that are "susceptible" to antibiotic in vitro. In the current study, we investigate specific purine biosynthetic pathways and stringent response mechanism(s) related to this life-threatening syndrome using genetic matched persistent and resolving MRSA clinical bacteremia isolates (PB and RB, respectively), and isogenic MRSA strain sets. We demonstrate that PB isolates (vs RB isolates) have significantly higher (p)ppGpp production, phenol-soluble-modulin expression, polymorphonuclear leukocyte lysis and survival, fibronectin/endothelial cell (EC) adherence, and EC damage. Importantly, an isogenic strain set, including JE2 parental, relP-mutant and relP-complemented strains, translated the above findings into significant outcome differences in an experimental endocarditis model. These observations indicate a significant regulation of purine biosynthesis on stringent response, and suggest the existence of a previously unknown adaptive genetic mechanism in persistent MRSA infection.

Published
2020

15. Sex-Specific Relationship Between Long-Term Maintenance of Physical Activity and Cognition in the Health ABC Study: Potential Role of Hippocampal and Dorsolateral Prefrontal Cortex Volume.

Author

Barha, Cindy K, Best, John R, Rosano, Caterina, Yaffe, Kristine, Catov, Janet M, and Liu-Ambrose, Teresa

Subjects
Neurosciences, Behavioral and Social Science, Acquired Cognitive Impairment, Neurodegenerative, Brain Disorders, Basic Behavioral and Social Science, Prevention, Dementia, Mind and Body, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Underpinning research, 1.2 Psychological and socioeconomic processes, 1.1 Normal biological development and functioning, Neurological, Mental health, Aged, Aged, 80 and over, Cognition, Cohort Studies, Executive Function, Exercise, Female, Healthy Aging, Hippocampus, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Neuroimaging, Prefrontal Cortex, Prospective Studies, Sex Characteristics, Walking, Sex differences, Clinical Sciences, Gerontology
Abstract

BackgroundPhysical activity (PA) is a promising strategy for the promotion of brain health, although substantial variation exists in the effects of PA at the individual level. Given the greater prevalence and faster progression of Alzheimer's disease in women compared to men, and known sex differences in brain architecture, analysis of sex differences in the relationship between PA, cognition, and brain region volumes is warranted.MethodsTo address this, we conducted secondary analyses of data from the Health, Aging, and Body Composition study. To determine whether longitudinal changes in PA over 10 years predicted declines in global cognitive functioning and executive functions and processing speed differently in males and females, latent growth curve modeling was utilized. Magnetic resonance imaging was performed at year 10, and the hippocampus and dorsolateral prefrontal cortex were identified as regions of interest.ResultsMaintaining PA over 10 years predicted less declines in executive functions and processing speed in females but not males. Maintaining PA over 10 years was significantly associated with greater volume of the left dorsolateral prefrontal cortex, a brain region involved in executive functions, in year 10 in females only. Maintaining physical activity was associated with better global cognitive function in both males and females, and also predicted volume of the left hippocampus, albeit in different directions with females showing a negative relationship and males showing a positive relationship.ConclusionsThese findings suggest that the relationship of PA with cognition and its neurobiological correlates differ by sex, with females apparently benefiting from PA to a greater extent than males. Development of personalized, tailored exercise recommendations to promote healthy brain aging should account for sex differences.

Published
2020

16. Role of e-cigarettes and pharmacotherapy during attempts to quit cigarette smoking: The PATH Study 2013-16

Author

Pierce, John P, Benmarhnia, Tarik, Chen, Ruifeng, White, Martha, Abrams, David B, Ambrose, Bridget K, Blanco, Carlos, Borek, Nicolette, Choi, Kelvin, Coleman, Blair, Compton, Wilson M, Cummings, K Michael, Delnevo, Cristine D, Elton-Marshall, Tara, Goniewicz, Maciej L, Gravely, Shannon, Fong, Geoffrey T, Hatsukami, Dorothy, Henrie, James, Kasza, Karin A, Kealey, Sheila, Kimmel, Heather L, Limpert, Jean, Niaura, Raymond S, Ramôa, Carolina, Sharma, Eva, Silveira, Marushka L, Stanton, Cassandra A, Steinberg, Michael B, Taylor, Ethel, Bansal-Travers, Maansi, Trinidad, Dennis R, Gardner, Lisa D, Hyland, Andrew, Soneji, Samir, and Messer, Karen

Subjects
Substance Misuse, Prevention, Clinical Research, Tobacco Smoke and Health, Drug Abuse (NIDA only), Cancer, Tobacco, 6.1 Pharmaceuticals, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, Evaluation of treatments and therapeutic interventions, Prevention of disease and conditions, and promotion of well-being, Respiratory, Good Health and Well Being, Adolescent, Adult, Behavior Therapy, Cigarette Smoking, Drug Therapy, Electronic Nicotine Delivery Systems, Female, Humans, Incidence, Longitudinal Studies, Male, Smoking Cessation, Time Factors, Tobacco Use Cessation Devices, Tobacco Use Disorder, United States, Vaping, Young Adult, General Science & Technology
Abstract

BackgroundMore smokers report using e-cigarettes to help them quit than FDA-approved pharmacotherapy.ObjectiveTo assess the association of e-cigarettes with future abstinence from cigarette and tobacco use.DesignCohort study of US sample, with annual follow-up.ParticipantsUS adult (ages 18+) daily cigarette smokers identified at Wave 1 (W1; 2013-14) of the PATH Study, who reported a quit attempt before W2 and completed W3 (n = 2443).ExposuresUse of e-cigarettes, pharmacotherapy (including nicotine replacement therapy), or no product for last quit attempt (LQA), and current daily e-cigarette use at W2.AnalysisPropensity score matching (PSM) of groups using different methods to quit.Outcome measures12+ months abstinence at W3 from cigarettes and from all tobacco (including e-cigarettes). 30+ days abstinence at W3 was a secondary outcome.ResultsAmong daily smokers with an LQA, 23.5% used e-cigarettes, 19.3% used pharmacotherapy only (including NRT) and 57.2% used no product. Cigarette abstinence for 12+ months at W3 was ~10% in each group. Half of the cigarette abstainers in the e-cigarette group were using e-cigarettes at W3. Different methods to help quitting had statistically comparable 12+ month cigarette abstinence at W3 (e-cigarettes vs no product: Risk Difference (RD) = 0.01, 95% CI: -0.04 to 0.06; e-cigarettes vs pharmacotherapy: RD = 0.02, 95% CI:-0.04 to 0.09). Likewise, daily e-cigarette users at W2 did not show a cessation benefit over comparable no-e-cigarette users and this finding was robust to sensitivity analyses. Abstinence for 30+ days at W3 was also similar across products.LimitationsThe frequency of e-cigarette use during the LQA was not assessed, nor was it possible to assess continuous abstinence from the LQA.ConclusionAmong US daily smokers who quit cigarettes in 2014-15, use of e-cigarettes in that attempt compared to approved cessation aids or no products showed similar abstinence rates 1-2 years later.

Published
2020

17. Leveraging incentives to increase HIV testing uptake among men: qualitative insights from rural Uganda.

Author

Ndyabakira, Alex, Getahun, Monica, Byamukama, Ambrose, Emperador, Devy, Kabageni, Stella, Marson, Kara, Kwarisiima, Dalsone, Chamie, Gabriel, Thirumurthy, Harsha, Kamya, Moses, Havlir, Diane, and Camlin, Carol

Subjects
Economic incentives, HIV testing, Loss aversion, Lottery, Men, Sub Saharan Africa, Adolescent, Adult, HIV Infections, Humans, Male, Mass Screening, Middle Aged, Motivation, Qualitative Research, Rural Population, Uganda, Young Adult
Abstract

BACKGROUND: Few studies have explored how economic incentives influence behavioral outcomes. This study aimed to identify pathways of action of an incentives-based intervention to increase mens participation in HIV testing. METHODS: The qualitative study was embedded in a randomized-controlled trial that compared effectiveness of gain-framed, loss-framed and lottery-based incentives to increase HIV testing among men. Following testing at a community health campaign, 60 in-depth interviews were conducted with men systematically sampled on the basis of age, incentive group, and campaign attendance. Data were coded deductively and inductively for thematic content analysis. RESULTS: Incentives addressed mens structural, interpersonal and individual-level barriers to testing: offered at convenient locations, incentives offset costs of testing, in lost wages, which are exacerbated when livelihoods required mobility. Interpersonal barriers included anticipated stigma/fear of disclosure, social obligations, and negative peer influences. Providing incentives in public settings provided social proof that prizes could be won, and facilitated social support and positive norms by promoting testing with trusted others. Incentives had little influence when men appraised prize values to be low, disbelieved they would win a prize, or were already intrinsically motivated to test. Yet, incentives provided a behavioral cue to action for many men who perceived themselves to be susceptible to HIV and perceived HIV disease to be severe, acting as secondary motivator for testing that sweetened the deal. CONCLUSION: Incentives can be an important lever to promote mens healthy behaviors in resource-poor settings. HIV testing in convenient, public settings, when paired with incentives, provides multiple pathways to stimulate mens testing uptake. TRIAL REGISTRATION: Registered with ClinicalTrials.gov on 08/10/2016, ID: NCT02890459. The first participant was enrolled on 11th April 2016.

Published
2019

18. Quorum sensing between bacterial species on the skin protects against epidermal injury in atopic dermatitis

Author

Williams, Michael R, Costa, Stephen K, Zaramela, Livia S, Khalil, Shadi, Todd, Daniel A, Winter, Heather L, Sanford, James A, O'Neill, Alan M, Liggins, Marc C, Nakatsuji, Teruaki, Cech, Nadja B, Cheung, Ambrose L, Zengler, Karsten, Horswill, Alexander R, and Gallo, Richard L

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Emerging Infectious Diseases, 2.1 Biological and endogenous factors, Aetiology, Skin, Animals, Bacteria, Bacterial Toxins, Coagulase, Dermatitis, Atopic, Epidermis, Homeostasis, Humans, Inflammation, Keratinocytes, Male, Mice, Inbred C57BL, Peptide Hydrolases, Peptides, Quorum Sensing, Staphylococcus, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

Colonization of the skin by Staphylococcus aureus is associated with exacerbation of atopic dermatitis (AD), but any direct mechanism through which dysbiosis of the skin microbiome may influence the development of AD is unknown. Here, we show that proteases and phenol-soluble modulin α (PSMα) secreted by S. aureus lead to endogenous epidermal proteolysis and skin barrier damage that promoted inflammation in mice. We further show that clinical isolates of different coagulase-negative staphylococci (CoNS) species residing on normal skin produced autoinducing peptides that inhibited the S. aureus agr system, in turn decreasing PSMα expression. These autoinducing peptides from skin microbiome CoNS species potently suppressed PSMα expression in S. aureus isolates from subjects with AD without inhibiting S. aureus growth. Metagenomic analysis of the AD skin microbiome revealed that the increase in the relative abundance of S. aureus in patients with active AD correlated with a lower CoNS autoinducing peptides to S. aureus ratio, thus overcoming the peptides' capacity to inhibit the S. aureus agr system. Characterization of a S. hominis clinical isolate identified an autoinducing peptide (SYNVCGGYF) as a highly potent inhibitor of S. aureus agr activity, capable of preventing S. aureus-mediated epithelial damage and inflammation on murine skin. Together, these findings show how members of the normal human skin microbiome can contribute to epithelial barrier homeostasis by using quorum sensing to inhibit S. aureus toxin production.

Published
2019

19. Sex-dependent effect of the BDNF Val66Met polymorphism on executive functioning and processing speed in older adults: evidence from the health ABC study

Author

Barha, Cindy K, Liu-Ambrose, Teresa, Best, John R, Yaffe, Kristine, Rosano, Caterina, and Health, Aging and Body Composition Study

Subjects
Biological Psychology, Psychology, Neurosciences, Aging, Genetics, Clinical Research, Neurological, Aged, Brain-Derived Neurotrophic Factor, Cognitive Aging, Cohort Studies, Executive Function, Female, Genotype, Humans, Male, Neurodegenerative Diseases, Polymorphism, Genetic, Prospective Studies, Sex Characteristics, Cognitive aging, Epidemiology, Brain-derived neurotrophic factor, Health, Aging and Body Composition Study, Clinical Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may be an important source of heterogeneity seen in cognitive aging, although the specific relationship between this polymorphism and cognition remains controversial and may depend on the sex of participants. We assessed 2668 older black and white adults and fit linear mixed models to digit symbol substitution test (DSST) performance assessed in years 0 (baseline), 4, 7, and 9 to examine the interaction between sex and BDNF genotype on the intercept (i.e., estimated baseline DSST) and change in DSST over 9 years, adjusted for covariates. Sex interacted with BDNF genotype to predict DSST intercept (F[1,1599] = 7.4, p < 0.01) and 9-year change (F[1,1183] = 4.1, p = 0.04) in white participants only. Initially, white male Val/Val carriers had lower DSST scores (37.6, SE = 0.8) in comparison with male Met carriers (difference, -1.7; 95% CI, -3.2 to -0.3) and female Val/Val carriers (difference, -5.6; 95% CI, -6.8 to -4.3). White female Met carriers showed a slower rate of change (annual rate of change = -0.6, SE = 0.1) in comparison with female Val/Val carriers (difference, -0.2; 95% CI, -0.4 to -0.02) and male Met carriers (difference, -0.3; 95% CI, -0.5 to -0.02). Our findings suggest that BDNF Val66Met and sex should be considered in future endeavors aimed at treating or preventing neurodegenerative disorders.

Published
2019

20. A Chemical Biology Approach to Model Pontocerebellar Hypoplasia Type 1B (PCH1B)

Author

François-Moutal, Liberty, Jahanbakhsh, Shahriyar, Nelson, Andrew DL, Ray, Debashish, Scott, David D, Hennefarth, Matthew R, Moutal, Aubin, Perez-Miller, Samantha, Ambrose, Andrew J, Al-Shamari, Ahmed, Coursodon, Philippe, Meechoovet, Bessie, Reiman, Rebecca, Lyons, Eric, Beilstein, Mark, Chapman, Eli, Morris, Quaid D, Van Keuren-Jensen, Kendall, Hughes, Timothy R, Khanna, Rajesh, Koehler, Carla, Jen, Joanna, Gokhale, Vijay, and Khanna, May

Subjects
Neurosciences, Genetics, 2.1 Biological and endogenous factors, Aetiology, Animals, Atrophy, Cerebellum, Disease Models, Animal, Down-Regulation, Exosome Multienzyme Ribonuclease Complex, Gene Knockdown Techniques, Humans, Isoquinolines, Molecular Docking Simulation, Mutation, Olivopontocerebellar Atrophies, Phenotype, Protein Binding, Protein Domains, RNA, RNA-Binding Proteins, Spinal Curvatures, Transcriptome, Up-Regulation, Zebrafish, Chemical Sciences, Biological Sciences, Organic Chemistry
Abstract

Mutations of EXOSC3 have been linked to the rare neurological disorder known as Pontocerebellar Hypoplasia type 1B (PCH1B). EXOSC3 is one of three putative RNA-binding structural cap proteins that guide RNA into the RNA exosome, the cellular machinery that degrades RNA. Using RNAcompete, we identified a G-rich RNA motif binding to EXOSC3. Surface plasmon resonance (SPR) and microscale thermophoresis (MST) indicated an affinity in the low micromolar range of EXOSC3 for long and short G-rich RNA sequences. Although several PCH1B-causing mutations in EXOSC3 did not engage a specific RNA motif as shown by RNAcompete, they exhibited lower binding affinity to G-rich RNA as demonstrated by MST. To test the hypothesis that modification of the RNA-protein interface in EXOSC3 mutants may be phenocopied by small molecules, we performed an in-silico screen of 50 000 small molecules and used enzyme-linked immunosorbant assays (ELISAs) and MST to assess the ability of the molecules to inhibit RNA-binding by EXOSC3. We identified a small molecule, EXOSC3-RNA disrupting (ERD) compound 3 (ERD03), which ( i) bound specifically to EXOSC3 in saturation transfer difference nuclear magnetic resonance (STD-NMR), ( ii) disrupted the EXOSC3-RNA interaction in a concentration-dependent manner, and ( iii) produced a PCH1B-like phenotype with a 50% reduction in the cerebellum and an abnormally curved spine in zebrafish embryos. This compound also induced modification of zebrafish RNA expression levels similar to that observed with a morpholino against EXOSC3. To our knowledge, this is the first example of a small molecule obtained by rational design that models the abnormal developmental effects of a neurodegenerative disease in a whole organism.

Published
2018

21. Role of Purine Biosynthesis in Persistent Methicillin-Resistant Staphylococcus aureus Infection

Author

Li, Liang, Abdelhady, Wessam, Donegan, Niles P, Seidl, Kati, Cheung, Ambrose, Zhou, Yu-Feng, Yeaman, Michael R, Bayer, Arnold S, and Xiong, Yan Q

Subjects
Microbiology, Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Emerging Infectious Diseases, Hematology, Biodefense, Biotechnology, Infectious Diseases, Sepsis, Prevention, Vaccine Related, Antimicrobial Resistance, Clinical Research, Aetiology, 2.2 Factors relating to the physical environment, Infection, Animals, Anti-Bacterial Agents, Bacteremia, Disease Models, Animal, Humans, Methicillin, Methicillin-Resistant Staphylococcus aureus, Purines, Rabbits, Staphylococcal Infections, MRSA, purine biosynthesis, and persistent endovascular infection, Medical and Health Sciences, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (PB) represents an important subset of S. aureus endovascular infections. In this study, we investigated potential genetic mechanisms underlying the persistent outcomes. Compared with resolving bacteremia (RB) isolates (defined as isolates associated with negative results of blood cultures 2-4 days after initiation of therapy), PB strains (defined as isolates associated with positive results of blood cultures ≥7 days after initiation of therapy) had significantly earlier onset activation of key virulence regulons and structural genes (eg, sigB, sarA, sae, and cap5), higher expression of purine biosynthesis genes (eg, purF), and faster growth rates, with earlier entrance into stationary phase. Importantly, an isogenic strain set featuring a wild-type MRSA isolate, a purF mutant strain, and a purF-complemented strain and use of strategic purine biosynthesis inhibitors implicated a causal relationship between purine biosynthesis and the in vivo persistent outcomes. These observations suggest that purine biosynthesis plays a key role in the outcome of PB and may represent a new target for enhanced efficacy in treating life-threatening MRSA infections.

Published
2018

22. HIV, Hepatitis B Virus, and Hepatitis C Virus Prevalence Among High-Risk Populations in South India

Author

Dinesha, Thongadi Ramesh, Boobalan, Jayaseelan, Sivamalar, Sathasivam, Solomon, Sunil S, Poongulali, Selvamuthu, Pradeep, Ambrose, Murugavel, Kailapuri G, Balakrishnan, Pachamuthu, Smith, Davey M, and Saravanan, Shanmugam

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Adult, Coinfection, Drug Users, Female, HIV, HIV Infections, Hepacivirus, Hepatitis B virus, Hepatitis, Viral, Human, Humans, India, Male, Middle Aged, Prevalence, Retrospective Studies, Risk, Sexuality, Virology, Clinical sciences
Published
2018

23. SaVanT: a web-based tool for the sample-level visualization of molecular signatures in gene expression profiles

Author

Lopez, David, Montoya, Dennis, Ambrose, Michael, Lam, Larry, Briscoe, Leah, Adams, Claire, Modlin, Robert L, and Pellegrini, Matteo

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Aetiology, 2.1 Biological and endogenous factors, Animals, Databases, Genetic, Gene Expression Profiling, Genetic Association Studies, Genomics, Humans, Organ Specificity, Phenotype, Software, Transcriptome, User-Computer Interface, Web Browser, Molecular signatures, Transcriptomic analysis, Tissue-specific expression, Heterogeneous samples, Visualization tools, Information and Computing Sciences, Medical and Health Sciences, Bioinformatics, Biological sciences, Biomedical and clinical sciences
Abstract

BackgroundMolecular signatures are collections of genes characteristic of a particular cell type, tissue, disease, or perturbation. Signatures can also be used to interpret expression profiles generated from heterogeneous samples. Large collections of gene signatures have been previously developed and catalogued in the MSigDB database. In addition, several consortia and large-scale projects have systematically profiled broad collections of purified primary cells, molecular perturbations of cell types, and tissues from specific diseases, and the specificity and breadth of these datasets can be leveraged to create additional molecular signatures. However, to date there are few tools that allow the visualization of individual signatures across large numbers of expression profiles. Signature visualization of individual samples allows, for example, the identification of patient subcategories a priori on the basis of well-defined molecular signatures.ResultHere, we generate and compile 10,985 signatures (636 newly-generated and 10,349 previously available from MSigDB) and provide a web-based Signature Visualization Tool (SaVanT; http://newpathways.mcdb.ucla.edu/savant ), to visualize these signatures in user-generated expression data. We show that using SaVanT, immune activation signatures can distinguish patients with different types of acute infections (influenza A and bacterial pneumonia). Furthermore, SaVanT is able to identify the prominent signatures within each patient group, and identify the primary cell types underlying different leukemias (acute myeloid and acute lymphoblastic) and skin disorders.ConclusionsThe development of SaVanT facilitates large-scale analysis of gene expression profiles on a patient-level basis to identify patient subphenotypes, or potential therapeutic target pathways.

Published
2017

24. Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.

Author

Guo, Zhijun, Sevrioukova, Irina, Denisov, Ilia, Zhang, Xia, Chiu, Ting-Lan, Thomas, Dafydd, Hanse, Eric, Cuellar, Rebecca, Grinkova, Yelena, Langenfeld, Vanessa, Swedien, Daniel, Stamschror, Justin, Alvarez, Juan, Luna, Fernando, Galván, Adela, Bae, Young, Wulfkuhle, Julia, Gallagher, Rosa, Petricoin, Emanuel, Norris, Beverly, Flory, Craig, Schumacher, Robert, OSullivan, M, Cao, Qing, Chu, Haitao, Lipscomb, John, Atkins, William, Gupta, Kalpna, Kelekar, Ameeta, Blair, Ian, Capdevila, Jorge, Falck, John, Sligar, Stephen, Poulos, Thomas, Georg, Gunda, Ambrose, Elizabeth, and Potter, David

Subjects
CYP3A4, autophagy, biguanide, breast cancer, cytochrome P450, electron transport chain, epoxyeicosatrienoic acid, hexyl-benzyl-biguanide, metformin, mitochondria, AMP-Activated Protein Kinases, Animals, Biguanides, Breast Neoplasms, Catalytic Domain, Cell Respiration, Cytochrome P-450 CYP3A, Estrogen Receptor alpha, Female, Gene Expression Regulation, Neoplastic, Gene Silencing, Heme, Humans, MCF-7 Cells, Membrane Potential, Mitochondrial, Mice, Mitochondria, Models, Molecular, Protein Transport
Abstract

The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs. Metformin bound to the active-site heme of CYP3A4 in a co-crystal structure, establishing CYP3A4 as a biguanide target. Structure-based design led to discovery of N1-hexyl-N5-benzyl-biguanide (HBB), which bound to the CYP3A4 heme with higher affinity than metformin. HBB potently and specifically inhibited CYP3A4 AA epoxygenase activity. HBB also inhibited growth of established ER+ mammary tumors and suppressed intratumoral mTOR. CYP3A4 AA epoxygenase inhibition by biguanides thus demonstrates convergence between eicosanoid activity in mitochondria and biguanide action in cancer, opening a new avenue for cancer drug discovery.

Published
2017

25. Long-term changes in time spent walking and subsequent cognitive and structural brain changes in older adults

Author

Best, John R, Rosano, Caterina, Aizenstein, Howard J, Tian, Qu, Boudreau, Robert M, Ayonayon, Hilsa N, Satterfield, Suzanne, Simonsick, Eleanor M, Studenski, Stephanie, Yaffe, Kristine, Liu-Ambrose, Teresa, and Health, Aging and Body Composition Study

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Clinical Sciences, Psychology, Neurosciences, Clinical Research, Biomedical Imaging, Brain Disorders, Behavioral and Social Science, Basic Behavioral and Social Science, Aging, Neurological, Aged, Aged, 80 and over, Apolipoprotein E4, Brain, Cognition, Diffusion Tensor Imaging, Female, Humans, Male, Neuroimaging, Time Factors, Walking, Physical activity, Hippocampus, Health, Aging and Body Composition Study, Neurology & Neurosurgery, Biological psychology
Abstract

Previous studies have shown that more active older adults have better cognition and brain health based on a variety of structural neuroimaging measures. Nevertheless, the effects of maintaining physical activity (PA) over an extended period of time on future changes in older adults' cognition and brain structure are unknown. Participants were 141 initially well-functioning community-dwelling older adults (aged 70-79 years at baseline; 60% female; 42% black) studied over a 13-year period. PA (self-reported time spent walking) was assessed annually from years 1 to 10. Magnetic resonance imaging with diffusion tensor was performed at years 10 and 13. Time spent walking decreased on average by 8.4% annually from year 1 to year 10. Independent of initial time spent walking, demographics, and APOE e4 status, better maintenance of time spent walking over the decade predicted less reduction in hippocampal volume (p = 0.03), smaller increases in global gray matter mean diffusivity and white matter axial diffusivity (p < 0.01), and maintenance of general cognitive performance (p < 0.01). Maintenance of cognitive performance was associated with smaller increases in white matter axial diffusivity (p < 0.01). PA at baseline and at year 10, as well as changes in PA over a 5-year period, was less predictive of future changes in brain structure and cognition. Thus, how PA levels change over longer periods of aging may be an important contributor to cognitive and neural protection.

Published
2017

26. White Paper: Developing Antimicrobial Drugs for Resistant Pathogens, Narrow-Spectrum Indications, and Unmet Needs.

Author

Boucher, Helen W, Ambrose, Paul G, Chambers, HF, Ebright, Richard H, Jezek, Amanda, Murray, Barbara E, Newland, Jason G, Ostrowsky, Belinda, and Rex, John H

Subjects
Infectious Diseases, Antimicrobial Resistance, Patient Safety, Clinical Research, Prevention, Emerging Infectious Diseases, Vaccine Related, Clinical Trials and Supportive Activities, Infection, Good Health and Well Being, Animals, Anti-Bacterial Agents, Drug Discovery, Drug Resistance, Multiple, Bacterial, Gram-Negative Bacteria, Humans, Randomized Controlled Trials as Topic, Research Design, antimicrobial resistance, antibiotic development, Infectious Diseases Society of America, Biological Sciences, Medical and Health Sciences, Microbiology
Abstract

Despite progress in antimicrobial drug development, a critical need persists for new, feasible pathways to develop antibacterial agents to treat people infected with drug-resistant bacteria. Infections due to resistant gram-negative bacilli continue to cause unacceptable morbidity and mortality rates. Antibacterial agents have been historically studied in noninferiority clinical trials that focus on a single site of infection (eg, complicated urinary tract infections, intra-abdominal infections), yet these designs may not be optimal, and often are not feasible, for study of infections caused by drug-resistant bacteria. Over the past several years, multiple stakeholders have worked to develop consensus regarding paths forward with a goal of facilitating timely conduct of antimicrobial development. Here we advocate for a novel and pragmatic approach and, toward this end, present feasible trial designs for antibacterial agents that could enable conduct of narrow-spectrum, organism-specific clinical trials and ultimately approval of critically needed new antibacterial agents.

Published
2017

27. Design and methods of the Population Assessment of Tobacco and Health (PATH) Study

Author

Hyland, Andrew, Ambrose, Bridget K, Conway, Kevin P, Borek, Nicolette, Lambert, Elizabeth, Carusi, Charles, Taylor, Kristie, Crosse, Scott, Fong, Geoffrey T, Cummings, K Michael, Abrams, David, Pierce, John P, Sargent, James, Messer, Karen, Bansal-Travers, Maansi, Niaura, Ray, Vallone, Donna, Hammond, David, Hilmi, Nahla, Kwan, Jonathan, Piesse, Andrea, Kalton, Graham, Lohr, Sharon, Pharris-Ciurej, Nick, Castleman, Victoria, Green, Victoria R, Tessman, Greta, Kaufman, Annette, Lawrence, Charles, van Bemmel, Dana M, Kimmel, Heather L, Blount, Ben, Yang, Ling, O'Brien, Barbara, Tworek, Cindy, Alberding, Derek, Hull, Lynn C, Cheng, Yu-Ching, Maklan, David, Backinger, Cathy L, and Compton, Wilson M

Subjects
Biomedical and Clinical Sciences, Public Health, Health Sciences, Cancer, Clinical Research, Substance Misuse, Tobacco, Prevention, Basic Behavioral and Social Science, Pediatric Research Initiative, Drug Abuse (NIDA only), Tobacco Smoke and Health, Behavioral and Social Science, 3.5 Resources and infrastructure (prevention), Prevention of disease and conditions, and promotion of well-being, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, Respiratory, Cardiovascular, Good Health and Well Being, Adolescent, Adult, Aged, Child, Female, Health Knowledge, Attitudes, Practice, Humans, Longitudinal Studies, Male, Middle Aged, Research Design, Smoking, United States, Young Adult, Public policy, Surveillance and monitoring
Abstract

BackgroundThis paper describes the methods and conceptual framework for Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study data collection. The National Institutes of Health, through the National Institute on Drug Abuse, is partnering with the Food and Drug Administration's (FDA) Center for Tobacco Products to conduct the PATH Study under a contract with Westat.MethodsThe PATH Study is a nationally representative, longitudinal cohort study of 45 971 adults and youth in the USA, aged 12 years and older. Wave 1 was conducted from 12 September 2013 to 15 December 2014 using Audio Computer-Assisted Self-Interviewing to collect information on tobacco-use patterns, risk perceptions and attitudes towards current and newly emerging tobacco products, tobacco initiation, cessation, relapse behaviours and health outcomes. The PATH Study's design allows for the longitudinal assessment of patterns of use of a spectrum of tobacco products, including initiation, cessation, relapse and transitions between products, as well as factors associated with use patterns. Additionally, the PATH Study collects biospecimens from consenting adults aged 18 years and older and measures biomarkers of exposure and potential harm related to tobacco use.ConclusionsThe cumulative, population-based data generated over time by the PATH Study will contribute to the evidence base to inform FDA's regulatory mission under the Family Smoking Prevention and Tobacco Control Act and efforts to reduce the Nation's burden of tobacco-related death and disease.

Published
2017

28. Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

Author

Gendron, Tania F, Chew, Jeannie, Stankowski, Jeannette N, Hayes, Lindsey R, Zhang, Yong-Jie, Prudencio, Mercedes, Carlomagno, Yari, Daughrity, Lillian M, Jansen-West, Karen, Perkerson, Emilie A, O'Raw, Aliesha, Cook, Casey, Pregent, Luc, Belzil, Veronique, van Blitterswijk, Marka, Tabassian, Lilia J, Lee, Chris W, Yue, Mei, Tong, Jimei, Song, Yuping, Castanedes-Casey, Monica, Rousseau, Linda, Phillips, Virginia, Dickson, Dennis W, Rademakers, Rosa, Fryer, John D, Rush, Beth K, Pedraza, Otto, Caputo, Ana M, Desaro, Pamela, Palmucci, Carla, Robertson, Amelia, Heckman, Michael G, Diehl, Nancy N, Wiggs, Edythe, Tierney, Michael, Braun, Laura, Farren, Jennifer, Lacomis, David, Ladha, Shafeeq, Fournier, Christina N, McCluskey, Leo F, Elman, Lauren B, Toledo, Jon B, McBride, Jennifer D, Tiloca, Cinzia, Morelli, Claudia, Poletti, Barbara, Solca, Federica, Prelle, Alessandro, Wuu, Joanne, Jockel-Balsarotti, Jennifer, Rigo, Frank, Ambrose, Christine, Datta, Abhishek, Yang, Weixing, Raitcheva, Denitza, Antognetti, Giovanna, McCampbell, Alexander, Van Swieten, John C, Miller, Bruce L, Boxer, Adam L, Brown, Robert H, Bowser, Robert, Miller, Timothy M, Trojanowski, John Q, Grossman, Murray, Berry, James D, Hu, William T, Ratti, Antonia, Traynor, Bryan J, Disney, Matthew D, Benatar, Michael, Silani, Vincenzo, Glass, Jonathan D, Floeter, Mary Kay, Rothstein, Jeffrey D, Boylan, Kevin B, and Petrucelli, Leonard

Subjects
Clinical Research, Neurodegenerative, Brain Disorders, Acquired Cognitive Impairment, Dementia, Neurosciences, ALS, Rare Diseases, Clinical Trials and Supportive Activities, Genetics, Neurological, Adult, Aged, Amyotrophic Lateral Sclerosis, Animals, Biomarkers, Brain, C9orf72 Protein, Cell Line, Dinucleotide Repeats, Humans, Induced Pluripotent Stem Cells, Leukocytes, Mononuclear, Longitudinal Studies, Mice, Middle Aged, Neurons, Oligonucleotides, Antisense, Prognosis, RNA, Biological Sciences, Medical and Health Sciences
Abstract

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

Published
2017

29. An Evaluation of the Longitudinal, Bidirectional Associations Between Gait Speed and Cognition in Older Women and Men

Author

Best, John R, Liu-Ambrose, Teresa, Boudreau, Robert M, Ayonayon, Hilsa N, Satterfield, Suzanne, Simonsick, Eleanor M, Studenski, Stephanie, Yaffe, Kristine, Newman, Anne B, and Rosano, Caterina

Subjects
Public Health, Health Sciences, Clinical Research, Behavioral and Social Science, Aging, Aged, Cognition Disorders, Executive Function, Female, Geriatric Assessment, Humans, Independent Living, Longitudinal Studies, Male, Pennsylvania, Risk Factors, Self Report, Sex Factors, Tennessee, Walking Speed, Cognition, Gait, Physical activity, Physical function, Health, Aging and Body Composition Study, Physical function., Clinical Sciences, Gerontology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundFew cohort studies have examined longitudinal associations between age-related changes in cognition and physical performance. Further, whether these associations differ for men versus women or can be attributed to differences in physical activity (PA) is unknown.MethodsParticipants were 2,876 initially well-functioning community-dwelling older adults (aged 70-79 years at baseline; 52% female; 39% black) studied over a 9-year period. Usual gait speed, self-reported PA, and two cognitive measures-Digit Symbol Substitution Test (DSST) and Mini-Modified Mental State examination (3MS)-were assessed years 0 (ie, baseline), 4, and 9.ResultsEarly decline between years 0 and 4 in gait speed predicted later decline between years 4 and 9 in performance on the 3MS (β = 0.10, p = .004) and on the DSST (β = 0.16, p < .001). In contrast, the associations between early decline in cognition and later decline in gait speed were weaker and were non-significant after correcting for multiple comparisons (β = 0.08, p = .019 for 3MS and β = .06, p = .051 for DSST). All associations were similar for women and men and were unaltered when accounting for PA levels.ConclusionsThe results indicate declining gait speed as a precursor to declining cognitive functioning, and suggest a weaker reciprocal process among older women and men.

Published
2016

30. Potent protection against H5N1 and H7N9 influenza via childhood hemagglutinin imprinting

Author

Gostic, Katelyn M, Ambrose, Monique, Worobey, Michael, and Lloyd-Smith, James O

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Pneumonia & Influenza, Influenza, Biodefense, Vaccine Related, Prevention, Emerging Infectious Diseases, Infection, Age Factors, Animals, Child, Genomic Imprinting, Global Health, Hemagglutinin Glycoproteins, Influenza Virus, Humans, Influenza A Virus, H5N1 Subtype, Influenza A Virus, H7N9 Subtype, Influenza, Human, Models, Statistical, Pandemics, Risk Assessment, Zoonoses, General Science & Technology
Abstract

Two zoonotic influenza A viruses (IAV) of global concern, H5N1 and H7N9, exhibit unexplained differences in age distribution of human cases. Using data from all known human cases of these viruses, we show that an individual's first IAV infection confers lifelong protection against severe disease from novel hemagglutinin (HA) subtypes in the same phylogenetic group. Statistical modeling shows that protective HA imprinting is the crucial explanatory factor, and it provides 75% protection against severe infection and 80% protection against death for both H5N1 and H7N9. Our results enable us to predict age distributions of severe disease for future pandemics and demonstrate that a novel strain's pandemic potential increases yearly when a group-mismatched HA subtype dominates seasonal influenza circulation. These findings open new frontiers for rational pandemic risk assessment.

Published
2016

31. Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy.

Author

Inkeles, Megan S, Teles, Rosane Mb, Pouldar, Delila, Andrade, Priscila R, Madigan, Cressida A, Lopez, David, Ambrose, Mike, Noursadeghi, Mahdad, Sarno, Euzenir N, Rea, Thomas H, Ochoa, Maria T, Iruela-Arispe, M Luisa, Swindell, William R, Ottenhoff, Tom Hm, Geluk, Annemieke, Bloom, Barry R, Pellegrini, Matteo, and Modlin, Robert L

Subjects
Humans, Leprosy, Leprosy, Lepromatous, Leprosy, Tuberculoid, Erythema Nodosum, Adolescent, Adult, Middle Aged, Female, Male, Gene Regulatory Networks, Young Adult, Transcriptome, Lepromatous, Tuberculoid
Abstract

Transcriptome profiles derived from the site of human disease have led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum, which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene coexpression modules by cell-type deconvolution. In lesions from tuberculoid leprosy patients, those with the self-limited form of the disease, dendritic cells were linked with MMP12 as part of a tissue remodeling network that contributes to granuloma formation. In lesions from lepromatous leprosy patients, those with disseminated disease, macrophages were linked with a gene network that programs phagocytosis. In erythema nodosum leprosum, neutrophil and endothelial cell gene networks were identified as part of the vasculitis that results in tissue injury. The present integrated computational approach provides a systems approach toward identifying cell-defined functional networks that contribute to host defense and immunopathology at the site of human infectious disease.

Published
2016

32. Higher dose corticosteroids in patients admitted to hospital with COVID-19 who are hypoxic but not requiring ventilatory support (RECOVERY)

Author

Obbina Abani, Ali Abbas, Fatima Abbas, Joshua Abbas, Kasim Abbas, Mustafa Abbas, Sadia Abbasi, Hakam Abbass, Alfie Abbott, Alison Abbott, Nabeel Abdallah, Ammar Abdelaziz, Ashraf Abdelaziz, Mohamed Abdelfattah, Bushra Abdelqader, Audrey Abdul, Basir Abdul, Siddiqui Abdul, Althaf Abdul Rasheed, Ajibode Abdulakeem, Rezan Abdul-Kadir, Abdullah Abdullah, Abdulfatahi Abdulmumeen, Rasheed Abdul-Raheem, Niyaz Abdulshukkoor, Kula Abdusamad, Yazeed Abed El Khaleq, Mai Abedalla, Abeer Abeer Ul Amna, Lynn Abel, Katrina Abernethy, Movin Abeywickrema, Chandra Abhinaya, Affyarsyah Abidin, Adebanke Aboaba, Abigail Aboagye-Odei, Christopher Aboah, Heba Aboelela, Hani Abo-Leyah, Karim Abouelela, Ahmed Abou-Haggar, Mahmoud Abouibrahim, Ahmed Abousamra, Mona Abouzaid, Miriam Abraham, Tizzy Abraham, Abraheem Abraheem, Judith Abrams, Rebecca Abrams, Hyacinth-John Abu, Ahmed Abu-Arafeh, Syed M Abubacker, Akata Abung, Yousuf Abusamra, Yaa Aceampong, Amaka Achara, Devikumar Acharya, Faustina Acheampong, Prince Acheampong, Sarah Acheampong, Janet Acheson, Shiella Achieng, Andres Acosta, Rebecca Acquah, Catherine Acton, Jacqueline Adabie-Ankrah, Paul Adair, Fiona Adam, Matthew Adam, Huzaifa Adamali, Marta Adamczyk, Carol Adams, Charlotte Adams, Daniel Adams, Kate Adams, Laura Adams, Nikkita Adams, Richard Adams, Tim Adams, Laura Adamu-Ikeme, Krishma Adatia, Kirsty Adcock, Lawrence Addai-Boampong, Afua Addo, Oluwatobi Adeagbo, Ade Adebiyi, Ogunlana Adedeji, Yewande Adegeye, Ken Adegoke, Vicki Adell, Sherna Adenwalla, Femi W Adeoye, Oluwasegun A Adesemoye, Emmanuel O Adewunmi, Adedamola Adeyanju, Joyce Adeyemi, Tenifayo Adeyemo, Binay Adhikari, Shanti A Adhikari, Rina Adhikary, Adhikarla Aditya, Patience Adjepong, Gabrielle Adkins, Adnan Adnan, Marguerite Adriaanse, John Aeron-Thomas, Debbie Affleck, Carmel Afnan, Muhammad Afridi, Patricia Afrim, Felicia Akua Afriyie, Zainab A Aftab, Meenakshi Agarwal, Rachel Agbeko, Chris Agbo, Sunil Aggarwal, Arameh Aghababaie, Laura Aguilar Jimenez, Jacqueline Afrakomah Agyekum, Kwame Agyen, Shafana Ahamed Sadiq, Mohamed H Ahammed Nazeer, Mohammad Ahmad, Syed Ahmad, Afshan Ahmed, Ashar Ahmed, Asim Ahmed, Basheer A R Ahmed, Bilal Ahmed, Forizuddin Ahmed, Hamze Ahmed, Hanad Ahmed, Irshad Ahmed, Khaled Ahmed, Khalil Ahmed, Liban Ahmed, Mahin Ahmed, Maria C Ahmed, Muhammad S Ahmed, Naseer Ahmed, Nausheen Ahmed, Osama Ahmed, Rajia A Ahmed, Rawya Ahmed, Rizwan Ahmed, Saif Ahmed, Sammiya Ahmed, Sana G Ahmed, Syed Ahmed, Syed H Ahmed, Roa Ahmed Ali, Bilal Ahmed Mohamud, Sana Ahmed, Sana Ahmer, Augustine Ahonia, Christine Aiken, Dhiraj Ail, Mark Ainsworth, Myriam Aissa, Lindianne Aitken, Bini Ajay, Abdulakeem Ajibode, Ayesha Ajmi, Nasim Akhtar, Nauman Akhtar, Suha Akili, Bolutito Akinbiyi, Oludoyinsola Akindolie, Yinka Akinfenwa, Olugbenga Akinkugbe, Ibrahim Akinpelu, Mohammad Akram, Olugbenro Aktinade, Uzayr Akudi, Ahmad S A R Al Aaraj, Asma Al Balushi, Majd Al Dakhola, Aladdin Al Swaifi, Eslam Al-Abadi, Adegoke Alabi, Narendra Aladangady, Mohamed Alafifi, Ayaz Alam, Sajid Alam, Abbas Al-Asadi, Kyriaki Alatzoglou, Paul Albert, Albertus Albertus, Lorraine Albon, Angela Alcala, Gemma Alcorn, Stephen Alcorn, Aggie Aldana, David Alderdice, Abdullah Aldesouki, Rayan Aldouri, Jonathan Aldridge, Nicolas Aldridge, Ram Maya Ale, Ana Alegria, Alison Alexander, Courtney Alexander, John Alexander, Peter D G Alexander, Julyan Al-fori, Laith Alghazawi, Osama Alhabsha, Bahij Al-Hakim, Rafil Alhameed, Mohammed Al-Hayali, Shams Al-Hity, Ali Ali, Amanda Ali, Asad Ali, Fawzia R Ali, Jawad Ali, Mariam Ali, Mohamed Ali, Mohammad Ali, Muhammad S Ali, Nayab Ali, Oudai Ali, Ramla Ali, Sakina Ali, Syed Ali, Emilio Aliberti, Jade Alin, Abid Alina, Analyn Alipustain, Bachti Alisjahbana, Fine Aliyuda, Katrin Alizadeh, Maithem Al-Jibury, Saba Al-Juboori, Majid Al-Khalil, Abdullah Alkhudhayri, Moutaz Alkhusheh, Fiona Allan, Nataliya Allan, Alison Allanson, Robert Allcock, Eireann Allen, Jade Allen, Kerry Allen, Louise Allen, Poppy Allen, Rebecca Allen, Sam Allen, Sharon Allen, Simon Allen, Tania Allen, Abiola Alli, Kathryn Allison, Bethan Allman, Helen K Allsop, Lynne Allsop, David Allsup, Amal F T Almahroos, Hassan Al-Moasseb, Magda Al-Obaidi, Lina Alomari, Akram Al-Rabahi, Bahar Al-Ramadhani, Zayneb Al-Saadi, Riyam Al-Sammarraie, Inji Alshaer, Rustam Al-Shahi Salman, Warkaq Al-Shamkhani, Fadia Alsheikh, Bashar Al-Sheklly, Sara Altaf, Amanda Alty, Mary Alvarez, Maria Alvarez Corral, Edward Alveyn, Maysaa Alzetani, Susan Amamou, Noor Amar, Sakkarai Ambalavanan, Robert Ambrogetti, Chris Ambrose, Amir Ameen, Amel Amelia Ganefianty, Katharine Ames, Maria R Amezaga, Allison Amin, Amina Amin, Kanish Amin, Syed Amin, Tara Amin, Badshah Amit, Amjad Amjad, Neelma Amjad, James Amoah-Dankwa, Victoria Amosun, Muhammad Amsal, Khaled Amsha, John Amuasi, Noelia Amutio Martin, Pugh Amy, Ann Anada, Atul Anand, Samantha Anandappa, Satya D Anantapatnaikuni, Ellen Anderson, Julie Anderson, Laura Anderson, Marina Anderson, Michelle Anderson, Nicola Anderson, Rachel Anderson, Rebecca Anderson, Rory Anderson, Samantha Anderson, Wendy Anderson, Prematie Andreou, Angela Andrews, Antonette Andrews, Jill Andrews, Joyann Andrews, Kanayochukwu Aneke, Andrew Ang, Wan Wei Ang, Tammy Angel, Aramburo Angela, Paola Angelini, Lazarus Anguvaa, Oleg Anichtchik, Millicent Anim-Somuah, Krishnan Aniruddhan, Jessica Annett, Louise Anning, Maldwyn Ansah, Patrick J Anstey, Rebekah Anstey, Alpha Anthony, Aaron Anthony-Pillai, Philip Antill, Zhelyazkova Antonina, Varghese Anu, Muhammad Anwar, Elena Apetri, Aristeidis Apostolopoulos, Sarah Appleby, Diane Appleyard, Maia F Aquino, Bianca Araba, Samuel Aransiola, Mariana Araujo, Ann Archer, Denise Archer, Samuel Archer, Simon Archer, Daniele Arcoria, Christian Ardley, Ana-Maria Arias, Oluwatoyin Aribike, Ryoki Arimoto, Charlotte Arkley, Charlotte Armah, Ilianna Armata, Jennifer Armistead, Adam Armitage, Ceri Armstrong, Maureen Armstrong, Sonia Armstrong, Wendy Armstrong, Philippa Armtrong, Heike Arndt, Clare Arnison-Newgass, David Arnold, Rachael Arnold, Andrew Arnott, Dhawal Arora, Kavan Arora, Pardeep Arora, Rishi Arora, Arslam Arter, Armena Arumaithurai, Ayush Arya, Rita Arya, Diptesh Aryal, Denisa Asandei, Adeeba Asghar, Malik Asghar, Arif Ashab, Catherine Ashbrook-Raby, Helen Ashby, Jan Ashcroft, John Ashcroft, Samuel Ashcroft, Georgia Asher, Zakariya Ashfak, Ayesha Ashfaq, Abdul Ashish, Dawn Ashley, Sally Ashman-Flavell, Sundar Ashok, Abd-El-Aziz Ashour, Muhammad Z Ashraf, Saima Ashraf, Mohammad B Ashraq, Deborah Ashton, Susan Ashton, Andrew Ashworth, Fiona J Ashworth, Rebecca Ashworth, Arshia Aslam, I Aslam, Suhail Aslam, Laura Aslett, Harshini Asogan, Atif Asrar, Omar Assaf, Raine Astin-Chamberlain, Deborah Athorne, Billie Atkins, Christopher Atkins, Stacey Atkins, John Atkinson, Vicki Atkinson, Abolaji Atomode, Brygitta Atraskiewicz, Abdul A Attia, Eva Attubato, Marie Attwood, Paula Aubrey, Zoltan Auer, Avinash Aujayeb, Aye Chan Thar Aung, Hnin Aung, Hnin Wint Wint Aung, Ko Ko Aung, Kyaw Thu Aung, Nwe Aung, Yin Aung, Zaw Myo Aung, Emily Austin, Karen Austin, Abdusshakur Auwal, Malcolm Avari, Miriam Avery, Nicholas Aveyard, Joanne Avis, Georgina Aviss, Cristina Avram, Paula Avram, Abuzar Awadelkareem, Gabriel Awadzi, Mahmoud Awaly, Atia Awan, Aszad Aya, Eman Ayaz, John Maximilian Ayerh, Amanda Ayers, Jawwad Azam, Ahmed Azeem, Mohammed Azharuddin, Ammar Aziz, Ghazala Aziz, Imran Aziz, N Aziz, Ali Azkoul, Ashaari Azman Shah, Giada Azzopardi, Hocine Azzoug, Fiyinfoluwa Babatunde, Melvin Babi, Babiker Babiker, Gayna Babington, Matthew Babirecki, Marta Babores, Adetona O Babs-Osibodu, Sammy Bacciarelli, Roudi Bachar, Michel-Elie Bachour, Alisjahbana Bachti, Gina Bacon, Jenny Bacon, Bibi Badal, Aysha Badat, Maryuma Bader, Gurpreet R Badhan, Shreya Badhrinarayanan, Joseph P Bae, Alice Baggaley, Amy Baggott, Graham Bagley, Dinesh Bagmane, Lynsey Bagshaw, Kasra Bahadori, Angela Bailey, James Bailey, Katie Bailey, Lindsey Bailey, Liz Bailey, Lucy Bailey, Maria A Bailey, Morgan Bailey, Pippa Bailey, Sarah Bailey, Hamish Baillie, J Kenneth Baillie, Jennifer Bain, Vikram Bains, David Baird, Eilidh Baird, Kevin Baird, Susan Baird, Tracy Baird, Yolanda Baird, Aiysha Bajandouh, Danielle C Baker, Evelyn Baker, Johanne Baker, Josephine Baker, Kenneth Baker, Mark Baker, Rebecca Baker, Terri-Anne Baker, Victoria Baker, Hugh Bakere, Nawar Bakerly, Michelle Baker-Moffatt, Ameet Bakhai, Nauman Bakhtiar, Panos Bakoulas, Dhanalakshmi Bakthavatsalam, Niranjan Balachandran, Andrea Balan, Prasath Balasingam, Theodosios Balaskas, Madhu Balasubramaniam, Nicola Balatoni, Alison Balcombe, Alexander Baldwin, Ashley Baldwin, Caron Baldwin, Danielle Baldwin, Fiona Baldwin, Rebekah Baldwin-Jones, Nichola Bale, James Balfour, Matthew Ball, Robert Ball, K Ballard, Ismael Balluz, Craig Balmforth, Emese Balogh, Abeir Baltmr, Amir Baluwala, Gabby Bambridge, Alasdair Bamford, Amy Bamford, Peter Bamford, Adefunke Bamgboye, Elizabeth Bancroft, Hollie Bancroft, Joyce Banda, Krishna Bandaru, Srini Bandi, Nageswar Bandla, Somaditya Bandyopadhyam, Amit Banerjee, Ritwik Banerjee, Santosh Baniya, Omar Bani-Saad, Harrison Banks, Luke Banks, Paul Banks, Claudia Bann, Helen Bannister, Oliver Bannister, Laura Banton, Tran Bao, Mariamma Baptist, Tanya Baqai, Ananya M Baral, Sharad Chandra Baral, Desislava Baramova, Russel Barber, Emma Barbon, Monica Barbosa, Jamie Barbour, Alexander Barclay, Amanda Barclay, Claire Barclay, George Bardsley, Stephanie Bareford, Shahedal Bari, Morris Barimbing, Amy Barker, Debbie Barker, Erandi Barker, Helen Barker, Joseph Barker, Leon Barker, Lesley Barker, Oliver Barker, Kerry Barker-Williams, Sinha Barkha, Juliana Barla, Gavin Barlow, Richard Barlow, Valerie Barlow, James Barnacle, Alex Barnard, Debi Barnes, Nicky Barnes, Rory Barnes, Theresa Barnes, Calum Barnetson, Amy Barnett, Ashton Barnett-Vanes, Prince Gyenti Barning, William Barnsley, Andrew Barr, David Barr, James Barr, Charlotte Barr, Nina Barratt, Shaney Barratt, Manuella Barrera, Amy Barrett, Fiona Barrett, Jessica Barrett, Sue Barrett, Esther Barrow, Jazz Bartholomew, Claire Bartlett, Georgina Bartlett, James Bartlett, Louise Bartlett, Shauna Bartley, Sandra Bartolmeu-Pires, Anna Barton, Greg Barton, Jill Barton, Lorna Barton, Rachael Barton, Rosaleen Baruah, Sonia Baryschpolec, Hannah Bashir, Archana Bashyal, Betsy Basker, Sudha Basnet, Buddha Basnyat, Ayten Basoglu, Alexander Basran, John Bassett, G Bassett, Chris Bassford, Bengisu Bassoy, Victoria Bastion, Anup Bastola, Anupam Basumatary, Precious Basvi, Jireh A Batac, Vipula R Bataduwaarachchi, Tristan Bate, Harry J Bateman, Kathryn Bateman, Vhairi Bateman, Eleanor Bates, Hayley Bates, Michelle Bates, Simon Bates, Sally Batham, Ana Batista, Amit Batla, Dushyant Batra, Harry Batty, Thomas Batty, Alice Batty, Miranda Baum, Rachel Baumber, Carina Bautista, Fareha Bawa, Tanveer Bawa, Fatima S Bawani, Simon Bax, Matt Baxter, Nicola Baxter, Zachary Baxter, Hannah Bayes, Lee-Ann Bayo, Farid Bazari, Rohit Bazaz, Ahmad Bazli, Laura Beacham, Wendy Beadles, Kirsten Beadon, Philip Beak, Andy Beale, Kathy Beard, Jack Bearpark, Alanna Beasley, Sandee Beattie, Karen Beaumont, Dawn Beaumont-Jewell, Theresa Beaver, Sarah Beavis, Christy Beazley, Sarah Beck, Virginia Beckett, Rosie Beckitt, Sarah Beckley, Heidi Beddall, Seonaid Beddows, Deborah Beeby, Sophia Beeby, Gail Beech, Michelle Beecroft, Nigel Beer, Sally Beer, Jane Beety, Gabriela Bega, Alison Begg, Susan Begg, Sara Beghini, Ayesha Begum, Salman Begum, Selina Begum, Teresa Behan, Roya Behrouzi, Jon Beishon, Claire Beith, James Belcher, Holly Belfield, Katherine Belfield, Ajay Belgaumkar, Dina Bell, Gareth Bell, Gillian Bell, Jessica Bell, Lauren Bell, Louise Bell, Nicholas Bell, Pippa Bell, Stephanie Bell, Jennifer Bellamu, Mary Bellamy, Tammy Bellamy, Arianna Bellini, Amanda Bellis, Fionn Bellis, Lesley Bendall, Naveena Benesh, Nicola Benetti, Leonie Benham, Guy Benison-Horner, Sarah Benkenstein, Tracey Benn, Ann Bennett, Caroline Bennett, Denise Bennett, Gillian Bennett, Kaytie Bennett, Kristopher Bennett, Lorraine Bennett, Miriam R Bennett, Sara Bennett, Karen Bennion, Gautham Benoy, Vivienne Benson, Andrew Bentley, James Bentley, Ian Benton, Eva Beranova, Matthew Beresford, Colin Bergin, Malin Bergstrom, Jolanta Bernatoniene, Thomas Berriman, Zoe Berry, Frida Best, Kimberley Best, Ans-Mari Bester, Yvonne Beuvink, Emily Bevan, Sarah Bevins, Tom Bewick, Andrew Bexley, Sonay Beyatli, Fenella Beynon, Arjun Bhadi, Sanjay Bhagani, Shiv Bhakta, Rekha Bhalla, Khushpreet Bhandal, Kulbinder Bhandal, Ashwin Bhandari, Lila Nath Bhandari, Sangam Bhandari, Jennifer Bhanich Supapol, Aashutosh Bhanot, Ravina Bhanot, Swati Bhasin, Abdul Bhat, Prashanth Bhat, Rahul Bhatnagar, Karan Bhatt, Janki Bhayani, Deepika Bhojwani, Parminder Bhuie, M S Bhuiyan, Salimuzzaman Bhuiyan, Anna Bibby, Fatima Bibi, Naheeda Bibi, Salma Bibi, Tihana Bicanic, Sarah Bidgood, Julie Bigg, Sarah Biggs, Alphonsa Biju, Andras Bikov, Sophie Billingham, Jessica Billings, Prof Binh, Alice Binns, Muhammad BinRofaie, Oliver Bintcliffe, Catherine Birch, Janine Birch, Jenny Birch, Katherine Birchall, Sam Bird, Sumedha Bird, Sarah Bird, Mark Birt, Claire Bishop, Kilanalei Bishop, Linda Bishop, Lisa Bishop, Karen Bisnauthsing, Nibedan Biswas, Mustapha Bittaye, Sahar Biuk, Karen Blachford, Ethel Black, Helen Black, Karen Black, Mairead Black, Polly Black, Virginia Black, Hayley Blackgrove, Bethan Blackledge, Joanne Blackler, Samantha Blackley, Helen Blackman, Caroline Blackstock, Cameron Blair, Francesca Blakemore, Helen Blamey, Alison Bland, Sujata Blane, Simon Blankley, Parry Blaxill, Katie Blaylock, Jane Blazeby, Natalie Blencowe, Ben Bloom, Jack Bloomfield, Angela Bloss, Alex Blowers, Samuel Blows, Hannah Bloxham, Susan Blrd, Louise Blundell, Andrew Blunsum, Mark Blunt, Tadhg Blunt, Ian Blyth, Kevin Blyth, Andrew Blythe, Karen Blythe, Kwabena Appiah Boahen, Marilyn Boampoaa, Sarah Board, Boniface Bobie, Karen Bobruk, Pritesh N Bodalia, Neena Bodasing, Marianne Boden, Tanya Bodenham, Gabriele Boehmer, Marta Boffito, Katherine Bohanan, Kristyna Bohmova, Niamh Bohnacker, Sumit Bokhandi, Maria Bokhar, Saba Bokhari, Sakina Bokhari, Syed O Bokhari, Idan Bokobza, Ambrose Boles, Clare Bolger, Candice Bonaconsa, Charlotte Bond, Helena Bond, Stuart Bond, Thomas Bond, Alice Bone, Georgia Boniface, Joseph Bonney, Lizzy Bonney, Lauren Booker, Sarah Boot, Matthew Boothroyd, Joanne Borbone, Naomi Borman, Samantha Bosence, Kirsty Bostock, Neil Botting, Fiona Bottrill, Hannah Bouattia, Laura Bough, Hayley Boughton, Zoe Boult, Tarek Boumrah, Miriam Bourke, Stephen Bourke, Michelle Bourne, Rachel Bousfield, Lucy Boustred, Alexandra Bowes, Amy Bowes, Philip Bowker, Tabitha Bowker, Helen Bowler, Louise Bowman, Simon Bowman, Rachel Bowmer, Angie Bowring, Helen Bowyer, Aileen Boyd, Jenny Boyd, Laura Boyd, Nicola Boyer, Namoi Boyle, Pauline Boyle, Rosalind Boyle, Louise Boyles, Leanna Brace, Abbey Bracken, Jodie Bradder, 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Bulbulia, Alex Bull, Damian Bull, Kate Bull, Rhian Bull, Thomas Bull, Emily Bullock, Susan Bullock, Naomi Bulteel, Kasun Bumunarachchi, Roneleeh Bungue-Tuble, Oliver Burbidge, Caroline Burchett, Dorota Burda, Christy Burden, Thomas G Burden, Mika Burgess, Richard Burgess, Sophia Burgess, Erlina Burhan, Hasan Burhan, Hannah Burke, Kerry Burke, Adrian Burman, Sara Burnard, Caroline Burnett, Sharon Burnett, Amy Burns, Collette Burns, James Burns, Karen Burns, Kiki Burns, Daniel Burrage, Kate Burrows, Claire Burston, Anna Burton, Ben Burton, Fiona Burton, Helen Burton, Matthew Burton, Mannaria Butar butar, Deborah Butcher, Aaron Butler, Emily Butler, Jessica Butler, Joanne Butler, Joshua Butler, Peter Butler, Susan Butler, Jenny Butler, Al-Tahoor Butt, Massawer Butt, Mohammad M Butt, Caryl Butterworth, Nicola Butterworth-Cowin, Robert Buttery, Tom Buttle, Heather Button, Daniel Buttress, Hannah Bye, Jane Byrne, Wendy Byrne, Victoria Byrne-Watts, Amanda Cabandugama, Luisa Cabrero, Simone Caddy, Ruth Cade, Anthony Cadwgan, Zhen Cahilog, Ajeng Cahyareny, Donna Cairney, James Calderwood, Darren Caldow, Emily Cale, Giorgio Calisti, Debbie Callaghan, Jennifer Callaghan, Claire Callens, Donaldson Callum, Caroline Calver, Melissa Cambell-Kelly, Tracey Camburn, David R Cameron, Eleanor Cameron, Fraser Cameron, Sheena Cameron, Christian Camm, Renee F D Cammack, Alison Campbell, Amy Campbell, Barbara Campbell, Bridget Campbell, Debbie Campbell, Helen Campbell, Hilary Campbell, Jonathan Campbell, Karen Campbell, Marion Campbell, Mark Campbell, Rachael Campbell, Robyn Campbell, Wynny Campbell, Quentin Campbell Hewson, Julie Camsooksai, Lisa Canclini, Shaula M Candido, Janie Candlish, Cielito Caneja, Alexandra Cann, Johnathon Cann, Ruby Cannan, Abigail Cannon, Emma Cannon, Michael Cannon, Petra Cannon, Vivienne Cannons, Ebnier Canonizado, Jane Cantliff, Ben Caplin, Santino Capocci, Noemi Caponi, Angelika Capp, Richard Capstick, Thomas Capstick, Catalin Caraenache, Aimee Card, Mary Cardwell, Charles Carey, Rachel Carey, Simon Carley, Ffion Carlin, Tammy Carlin, Samantha Carmichael, Margaret Carmody, Mandy Carnahan, Charlotte Caroline, Jodi Carpenter, Sharon Carr, Anna Carrasco, Zoe Carrington, Amy Carroll, Anne Carroll, Paul Carroll, Rachel Carson, Cindy Cart, Emma Carter, Jonathan Carter, Michael Carter, Natasha Carter, Paul Carter, Penny Carter, Douglas Cartwright, Jo-Anne Cartwright, Claire Carty, Lotoyah Carty, Jaime Carungcong, Charlotte Carver, Emma Carver, Rachel Carver, Susan Casey, Annie Cassells, Teresa Castiello, Gail Castle, Bridget Castles, Melanie Caswell, Ana Maria Catana, Heidi Cate, Anelise Catelan Zborowski, Susanne Cathcart, Katrina Cathie, Darwin Catibog, Christine Catley, Laura Catlow, Matthew Caudwell, Anna Cavazza, Ashleigh Cave, Luke Cave, Simon Cavinato, Frianne Cawa, Kathryn Cawley, Chloe Caws, Kay Cawthorne, Hankins Cendl, Hannah Century, Jeva Cernova, Mansur Cesay, Ed Cetti, Stephanie Chabane, Manish Chablani, Cathleen Chabo, Cyril J 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Samantha Clarke, Sheron Clarke, Alleyna Claxton, Louis Claxton, Kate Clay, Catherine Clayton, Elizabeth Clayton, Olivia Clayton, Jill Clayton-Smith, Bethan Clearyb, Chris Cleaver, Rose Cleeton, Ian Clement, Carlota Clemente de la Torre, Jayne Clements, Suzanne Clements, Sue Clenton, Sheryl Cliff, Rachael Clifford, Sarah Clifford, Amelia Clive, Jonathan Clouston, Vincent Clubb, Samantha Clueit, Lisa Clutterbuck, Andrea Clyne, Michelle Coakley, Peter G L Coakley, Kathryn Cobain, Alexandra Cochrane, Patricia Cochrane, Laura Cockayne, Maeve Cockerell, Helen Cockerill, Shirley Cocks, Rachel Codling, Adam Coe, Samantha Coetzee, David Coey, Danielle Cohen, Jonathan Cohen, Oliver Cohen, David Cohen, Mike Cohn, Louise Coke, Olutoyin Coker, Nicholas Colbeck, Roghan Colbert, Esther Cole, Jade Cole, Joby Cole, Garry Coleman, Matt Coleman, Nick Coleman, Holly Coles, Macleod Colin, Alicia Colino-Acevedo, Julie Colley, Kathleen Collie, Alexandra Collier, Danielle Collier, Dawn Collier, Heather Collier, Terry Collingwood, Paul Collini, Emma Collins, Jaimie Collins, Joanne Collins, Kayleigh Collins, Megan Collins, Nicola Collins, Sally Collins, Vicky Collins, Andrew Collinson, Bernadette Collinson, Jennifer Collinson, Matthew Collis, Madeleine Colmar, Hayley E Colton, James Colton, Katie Colville, Carolyn Colvin, Edward Combes, David Comer, Alison Comerford, Dónal Concannon, Alison Condliffe, Robin Condliffe, Emma Connell, Lynne Connell, Natalie Connell, Karen Connelly, Gavin Connolly, Emma Connor, Antonia Conroy, Kevin Conroy, Veronica Conteh, Rory Convery, Francesca Conway, Grainne Conway, Rhiannon Conway, Robert Conway, Jo-Anna Conyngham, Amanda Cook, Amber Cook, Colette Cook, Eloise Cook, Gemma Cook, Helen Cook, Julie Cook, Martin Cook, Sarah Cook, Danielle Cooke, Graham Cooke, Hannah Cooke, Justin Cooke, Katrina Cooke, Tim Cooke, Vikki Cooke, Adele Cooper, Chris Cooper, David Cooper, Helen Cooper, Jamie Cooper, Lauren Cooper, Nick Cooper, Rowena Cooper, Samantha Cooray, Thomas Cope, Sinead Corbet, Carolyn Corbett, Ailsa Corbishley, John Corcoran, Chris Cordell, Jessica Cordle, Alasdair Corfield, John Corless, Alison Corlett, Joe Cornwell, Michael Cornwell, Diana Corogeanu, Aisling Corr, Mirella Corredera, Ruth Corrigan, P Corry, Rita Corser, Jon Cort, Denise Cosgrove, Tracey Cosier, Patricia Costa, Telma Costa, Charlie Coston, Susannah Cotgrove, Zoe Coton, Lisa-Jayne Cottam, Rhiannon Cotter, Donna Cotterill, Caroline Cotton, George Couch, Martina Coulding, Andrew Coull, David Counsell, David Counter, Cherry Coupland, Ellie Courtney, Julia Courtney, Rebecca Cousins, Amanda J Coutts, Alexander Cowan, Elena Cowan, Richard Cowan, Richard Cowell, Louise Cowen, Steve Cowman, Amanda Cowton, Ellie Cox, Emma Cox, Giles Cox, Helen Cox, Karina Cox, Miriam Cox, Karen Coy, Andrea Cradduck-Bamford, Hannah Craig, Jayne Craig, John Craig, Victoria Craig, Felicity Craighead, Matthew Cramp, Hayley Cranston, Sheetal S Crasta, Jacolene Crause, Angie Crawford, Emma 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Czekaj, Patrycja Czylok, Shane D'Souza, Joana da Rocha, Mohammed Dafalla, Andrew Dagens, Helen Daggett, Jacqui Daglish, Sandeep Dahiya, Anne Dale, Katie Dale, Michaela Dale, Sam Dale, Susan Dale, Jolyon Dales, Umberto D'Alessandro, Helen Dalgleish, Helen Dallow, Carlo D'aloia, Dermot Dalton, Morag Dalton, Zoe Daly, Mansi Damani, Eleanor Damm, Akila Danga, Joanne Dangerfield, Amelia Daniel, Priya Daniel, Allison Daniels, Adela Dann, Kwaku Gyasi Danso, Sandra Danso-Bamfo, Quang Tung Dao, Suzanne Darby, Alex Darbyshire, Janet Darbyshire, Paul Dargan, Paul Dark, Kate Darlington, Sarah Darnell, Thomas Darton, Guledew Darylile, Avisnata Das, Manjusha Das, Sukamal Das, Martin Daschel, Joanne Dasgin, Dibyendu Datta, Anna Daunt, Vaishali Dave, Emily Davenport, Mark Davey, Miriam Davey, Molly Davey, Mini David, Alexander Davidson, Laura Davidson, Neil Davidson, Richard Davidson, Albert Davies, Alison Davies, Amanda Davies, Amy Davies, Angela Davies, Bethan Davies, Caroline Davies, Carolyn 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Souza, Anthony De Soyza, Natasha de Vere, Johannes de Vos, Bethan Deacon, Sharon Dealing, Anna Dean, Julie Dean, Katrina Dean, Stephen Dean, Tessa Dean, Jill Deane, James Dear, Effie Dearden, Catherine Deas, Samuel Debbie, Gabor Debreceni, Vashist Deelchand, Matthew Deeley, Joanne Deery, Emmanuel Defever, Manuela Del Forno, Arnold Dela Rosa, Gonzalo De-La-Cedra, Amanda Dell, Carrie Demetriou, David DeMets, Jane Democratis, Jacqueline Denham, Emmanuelle Denis, Laura Denley, Craig Denmade, Alexandra Dent, Kathy Dent, Martin Dent, Elise Denton, Tom Denwood, Nishigandh Deole, Darshita Depala, Maria Depante, Susan Dermody, Amisha Desai, Asmita Desai, Purav Desai, Sanjeev Deshpande, Vai Deshpande, Sirjana Devkota, Usha Devkota, Debbie Devonport, Matthew Devonport, Prakash Dey, Vishal Dey, Rogin Deylami, Kevin Dhaliwal, Sundip Dhani, Amandeep Dhanoa, Mili Dhar, Ankush Dhariwal, Dawpadee Dharmasena, Devesh Dhasmana, Ekanjali Dhillon, Reiss Dhillon, Syra Dhillon, Meghnath Dhimal, Dipali Dhiru, 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Patrick Easton, Ruth Eatough, Oluwadamilola Ebigbola, Martin Ebon, Alison Eccles, Sinan Eccles, Chloe Eddings, Michael Eddleston, Maureen Edgar, Katharine Edgerley, Nicholas Edmond, Mary Edmondson, Tracy Edmunds, Abby Edwards, Alexandra Edwards, Catherine Edwards, Joy Edwards, Kennedy Edwards, Mandy Edwards, Martin Edwards, Sophie Edwards, Jenny Eedle, Aline Eggink, Dawn Egginton, Sam Eggleston, Loveth Ehiorobo, Sarah Eisen, Ugochukwu Ekeowa, Mohamed Ekoi, Ayomide Ekunola, Soha El Behery, Nagla Elashhar, Lisa Elawamy, Mohamed Elbeshy, Kate El-Bouzidi, Jennifer Elder, Mohammed El-Din, Emma Eldridge, Diana Eleanor, Uchenna Elenwa, Ibrahim Eletu, Eman Elfar, Mayy Magdy Elgamal, Amr Elgohary, Mohamed A A Elhadi, Stellios Elia, Jennifer Elias, Tania Elias, Nadia Elkaram, Andrew V Elkins, Julie Ellam, Nikki Ellard, Laura N Ellerton, Lucy Elliot, Amy Elliott, Fiona Elliott, Kerry Elliott, Scott Elliott, Sian Elliott, Annie Ellis, Christine Ellis, Kaytie Ellis, Leila Ellis, Rupert Ellis, Tak-Yan Ellis, Yvette Ellis, Alison C Ellwood, Rahma Elmahdi, Einas Elmahi, Hannah-May Elmasry, Mohammed El-Naggar, Najla Elndari, Omer Elneima, Mohamed Elokl, Ahmed Elradi, Mohamed Elsaadany, Mohammed A S A Elsayed, Sally El-Sayeh, Hana El-Sbahi, Mohammad Elsebaei, Tarek Elsefi, Karim El-Shakankery, Alguili Elsheikh, Hosni El-Taweel, Sarah Elyoussfi, Jonathan Emberey, Jonathan R Emberson, John Emberton, Anna Emery, Julian Emmanuel, Ingrid Emmerson, Michael Emms, Florence Emond, Marieke Emonts, Nicu Enachi, Dickson Enenche, Angila Engden, Katy English, Emma Entwistle, Hene Enyi, Marios Erotocritou, Peter Eskander, Hanif Esmail, Fatheha Essa, Brynach Evans, Chris Evans, Debra Evans, E Evans, Emrys Evans, Gail Evans, Gareth Evans, Isabel Evans, Jack Evans, Jacqueline Evans, Jennifer Evans, John Evans, Jolanta Evans, Lisa Evans, Lynn Evans, Mim Evans, Morgan Evans, Ranoromanana Evans, Sharon Evans, Sian Evans, Teriann Evans, Tomos Evans, Caroline Everden, Serenydd Everden, Lynette Every, Hayley Evison, Lynsey Evison, Chiamaka Ezenduka, Jacqueline Faccenda, Leila Fahel, Youstina Fahmay, Ian Fairbairn, Sara Fairbairn, Terry Fairbairn, Andy Fairclough, Louise Fairlie, Mark Fairweather, Anne Fajardo, Naomi Falcone, Euan Falconer, John Fallon, Andrea Fallow, David Faluyi, Victoria Fancois, Ayaan Farah, Muna Farah, Qayyum Farah, Nowin Z Fard, Leila Fares, Amr Farg, Adam Farmer, Katie Farmer, Toni Farmery, Samantha Farnworth, Faiyaz Farook, Hadia Farooq, Sidrah Farooq, Fiona Farquhar, Holly Farr, Aaron Farrell, Barbara Farrell, Fayed Farrukh, James Farthing, Syeda Farzana, Rahmatu Fasina, Azam Fatemi, Mina Fatemi, Suman Fathima, Nibah Fatimah, Maria Faulkner, Saul N Faust, Clair Favager, Joe Fawke, Sinmidele Fawohunre, Abul Fazal, Aisthath Fazleen, Simon Fearby, Connie Fearnley, Alex Feben, Federico Fedel, Daria Fedorova, Christopher Fegan, Mae Felongo, Lynsey Felton, Tim Felton, Kate Fenlon, Andrea Fenn, Ruth Fennelly, Isabelle Fenner, Ciara Fenton, Melisa Fenton, Gloria Ferenando, Cameron Ferguson, Jenny Ferguson, Kathryn Ferguson, Katie Ferguson, Susan Ferguson, Susie Ferguson, Victoria Ferguson, Denzil Fernandes, Candida Fernandez, Eduardo Fernandez, Maria Fernandez, Sonia Fernandez Lopez, Jaime Fernandez Roman, Callum J Fernando, Jessica Fernando, Ahmed Feroz, Pietro Ferranti, Thais Ferrari, Eleanor Ferrelly, Alexandra Ferrera, Emma Ferriman, Sheldon Ferron, Nicholas Fethers, Ben Field, Janet Field, Rebecca Field, Karen Fielder, Lindsey Fieldhouse, Andra Fielding, Julie Fielding, Sarah Fielding, Asma Fikree, Santos Filipa, Sarah A Filson, Shona Finan, Sarah Finbow, Deborah J Finch, Joanne Finch, Laurie Finch, Simon Finch, Spencer Finch, Natalie Fineman, Jim Finlayson, Lauren Finlayson, Adam Finn, Joanne Finn, Dylan Finnerty, Clare Finney, Deborah Finucane, Sofia Fiouni, Jo Fiquet, Promise Firi, James Fisher, Neil Fisher, Daniel Fishman, Krystofer Fishwick, Carolyn Fitton, Felicity Fitzgerald, Fiona Fitzgerald, Karen Fitzjohn, Jan Flaherty, Michael Flanagan, Charles Flanders, Nikolaos Flaris, Gail Fleming, Julie Fleming, Lucy Fleming, Paul Fleming, William Flesher, Alison Fletcher, Anna Fletcher, Jonathan Fletcher, Lucy Fletcher, Simon Fletcher, Sophie Fletcher, Fiona Flett, Karen Flewitt, Sarah Flockhart, Christopher Flood, Ian Floodgate, Jonathan Flor, Vincent Florence, Mary Flowerdew, Sharon Floyd, Margaret J Flynn, Rachel Flynn, Claire Foden, Adama Fofana, Georgina Fogarty, Paul Foley, Linda Folkes, Tracey Fong, Daniela M Font, Aiwyne Foo, Jane Foo, Andrew Foot, Helen R Foot, Jayne Foot, Jane Forbes, Amber Ford, Jamie Ford, Imogen Fordham, Jennifer Foreman, Matthew Forester, Mohammad Forkan, Caroline Fornolles, Adam Forrest, Ellie Forsey, Miranda Forsey, Thomas Forshall, Elliot Forster, Abigail Forsyth, Julian Forton, Conrad Foster, Emily Foster, Joseph Foster, Rachel A Foster, Tracy Foster, Angela Foulds, Ian Foulds, Folakemi Fowe, Natasha Fowkes, Emily Fowler, Robert Fowler, Stephen Fowler, Amy Fox, Claire Fox, Heather Fox, 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Giokanini-Royal, Anna Gipson, Barbie Giri, Joanna Girling, Rhian Gisby, Angelena Gkioni, Aikaterini Gkoritsa, Effrossyni Gkrania-Klotsas, Amy Gladwell, James Glanville, Jessica Glasgow, Susannah Glasgow, Jon Glass, Lynn Glass, Sharon Glaysher, Lisa Gledhill, Eleanor Glenday, Ana Glennon, Jodie Glossop, John Glover, Kyle Glover, Michelle Glover, Jan Glover Bengtsson, Deborah Glowski, Sharon Glynn, Chevanthy Gnanalingam, Julie Goddard, Wendy Goddard, Emily Godden, Jo Godden, Sarah Godlee, Emma Godson, Gillian Godwin, Sukanya Gogoi, Aiky Goh, Manjinder Gohel, Rebeca Goiriz, Sriya Gokaraju, Raphael Goldacre, Arthur Goldsmith, Portia Goldsmith, Darren Gomersall, Lucia Gomez, Raquel Gomez-Marcos, Ali Gondal, Celia Gonzalez, Jack Goodall, Vicky Goodall, Bob Goodenough, Anna Goodfellow, Laura Goodfellow, James Goodlife, Camelia Goodwin, Elizabeth Goodwin, Jayne Goodwin, Paula Goodyear, Rajiv Gooentilleke, Michelle Goonasekara, Sheila Gooseman, Shameer Gopal, Chris Gordon, Sally Gordon, Robin 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Ruth Hartley, Tom Hartley, William Hartrey, Phillipa Hartridge, Stuart Hartshorn, Alice Harvey, Angela Harvey, Anna Harvey, Max Harvey, Catherine Harwood, Helen Harwood, Zoe Harzeli, Brigitte Haselden, Kazi Hashem, Mohammed Hashimm, Tadaaki Hashimoto, Imranullah Hashmi, Jack Haslam, Zena Haslam, Grace Hasnip, Adil Hassan, Ali Hassan, Amro Hassan, Awab Hassan, Zeinab Hassan, Sapna Hassasing, Jane Hassell, Philip Hassell, Alex Hastings, Bethany Hastings, Janice Hastings, Sarah Hathaway-Lees, Jonathan Hatton, Jennifer Hau, May Havinden-Williams, Stefan Havlik, Daniel B Hawcutt, Kadean Hawes, Liz Hawes, Nicola Hawes, Lydia Hawker, Annie Hawkins, Joe Hawkins, Nancy Hawkins, W John Hawkins, Dan Hawley, Ed Hawley-Jones, Edward Haworth, Alasdair W Hay, Cathy Hay, Amna Hayat, Jamal Hayat, Mohamed-Riyal Hayathu, Anne Hayes, Jonas Hayes, Kate Hayes, Melony Hayes, Fiona Hayes, Patrick Hayle, Chloe Haylett, Antara Hayman, Melanie Hayman, Matthew Haynes, Richard Haynes, Rachel Hayre, Carole Hays, Sarah Haysom, James Hayward, Patrick Haywood, Hazel Haywood Hasford, Tracy Hazelton, Phoebe Hazenberg, Zhengmai He, Elizabeth Headon, Carrie Heal, Brendan Healy, Jessica L Healy, Amy Hearn, David Heasman, Angela Heath, Debbie Heath, Rowan Heath, Diane Heaton, Adam Heavens, Kerry Hebbron, Catherine Heckman, Gemma Hector, Sadie Heddon, Andy Hedges, Katrine Hedges, Cheryl Heeley, Elaine Heeney, Richard Heinink, Rajdeep Heire, Ingvild Helgesen, Joanne Hemingway, Ulla Hemmila, Beth Hemmings, Scott Hemphill, Deborah Hemsley, Abigail Henderson, Eilidh Henderson, Jennifer Henderson, Steven Henderson, Joanne Henry, Karol Henry, Lavinia Henry, Margo Henry, Natalie Henry, David Henshall, Gillian Herdman, Rosaleen Herdman-Grant, Morag Herkes, Lucas E Hermans, Fe Marie Hernandez, Emma Heron, Lisa Heron, William Herrington, Emilia Heselden, Peta Heslop, Tracey Heslop, Simon Hester, Emily Hetherington, Joseph Hetherington, Chamila Hettiarachchi, Pramodh Hettiarachchi, Hayley Hewer, John Hewertson, Anna Hewetson, Sue Hewins, Nicola Hewitson, Claire Hewitt, Davina Hewitt, Richard Hewitt, Samuel Hey, Robert S Heyderman, Mathis Heydtmann, Joseph Heys, Jonathan Heywood, Meg Hibbert, John Hickey, Naomi Hickey, Peter Hickey, Nicky Hickman, Alex Hicks, Jenny Hicks, Scott R Hicks, Phan Thi Thu Hien, Daniel Higbee, Lucy Higgins, Andrew Higham, Martin Highcock, Judith Highgate, Mondy Hikmat, Amanda Hill, Helen Hill, Joanne Hill, Lisa Hill, Lucy Hill, Phoebe Hill, Uta Hill, Annette Hilldrith, Catherine Hillman-Cooper, Jon Hilton, Zoe Hilton, Sarah Hinch, Andrew Hindle, Esther Hindley, Alice Hindmarsh, Paul Hine, Kim Hinshaw, Clare Hird, Claire Hirst, Lindsay Hirst, Jemma Hives, Htet M Hlaing, Benson Ho, David K K Ho, Rosemary Ho, Michaela Hoare, David Hobden, Gill Hobden, Maria Hobrok, Simon Hobson, Christopher Hodge, Simon Hodge, Lesley Hodgen, George Hodgetts, Holly Hodgkins, Sally Hodgkinson, David Hodgson, Helen Hodgson, Luke Hodgson, Sheila Hodgson, Gemma Hodkinson, Kenneth Hodson, 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Elizabeth Horsley, Sarah Horton, Jane Hosea, Toby Hoskins, Muhammad S Hossain, Rashed Hossain, Maxine Hough, Sarah Hough, Catherine Houghton, Kathryn Houghton, Rebecca Houlihan, Kay Housely, Hamish Houston, Roseanna Hovvels, Lee How, Laura Howaniec, Joanne Howard, Kate Howard, Laura Howard, Linda Howard, Lucy Howard, Megan Howard, Sarah Howard, Stuart Howard, Richard Howard-Griffin, Louise Howard-Sandy, Serena Howe, Alice Howell, Mark Howells, Lyn Howie, Kerry Howlett, Sophie Howlett, Ruth Howman, Josh Hrycaiczuk, Hein Htet, Naing Z Htoon, Su Htwe, Ying Hu, Chiang O H Huah, Sylvia Huang, Kelly Hubbard, Abby Huckle, Shahzya Huda, Alison Hudak, Lisa Hudig, Heather Hudson, Suzanne Hudson, Oli Hudson, Alison Hufton, Connor Huggins, Alistair Hughes, Caitlin Hughes, Emma Hughes, Gareth Hughes, Heather Hughes, Luke Hughes, Martin Hughes, Rachel Hughes, Rebecca Hughes, Samantha Hughes, Stephen Hughes, Vikki Hughes, Wesley Hughes, Lukas Huhn, Ching Hui, Ruth Hulbert, Diana Hull, Grace Hull, Robert Hull, Amanda Hulme, Peter Hulme, Wendy Hulse, George Hulston, Ryan Hum, Megan Hume, Charlotte Humphrey, Alasdair Humphries, Amy Humphries, Joanne Humphries, Charlotte Hunt, Fiona Hunt, Jane Hunt, Jonquil Hunt, Kristen Hunt, Luke Hunt, Molly Hunt, Sophie Hunt, Alexandra Hunter, Catherine Hunter, Ewan Hunter, Karl Hunter, Neil Hunter, Ross Hunter, Sophie Hunter, George Huntington, Fuad Huq, Elizabeth Hurditch, Judith Hurdman, Cian Hurley, Katrina Hurley, Mohammed A Husain, Syeda Y Husaini, Coralie Huson, Afreen Hussain, Chreif Hussain, Ibraar Hussain, Ifza Hussain, Mohammad Hussain, Mohammed Hussain, Muhammad Hussain, Reda Hussain, Rizwana Hussain, Samia Hussain, Sanniah Hussain, Yasmin Hussain, Mohammed Hussam El-Din, Samahir F E M Hussein, Ziad Hussein, Rebecca Hussey, Adiel Haqiq Hussien, Anja Hutchinson, Camille Hutchinson, Dorothy Hutchinson, Elizabeth Hutchinson, John Hutchinson, Claire Hutsby, Paula Hutton, Nguyen Quang Huy, Thuong Huyen, Tran Bang Huyen, Nguyen Thi Huyen 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Julie Jones, Kate E Jones, Kimberly Jones, Laura Jones, Laura M Jones, Louise Jones, Mathew Jones, Nancy Jones, Nicola Jones, Olivia Jones, Paul Jones, Philip H Jones, Rhianna Jones, Ruth E Jones, Samantha Jones, Sophie Jones, Stefanie Jones, Steve Jones, Susan Jones, Taya Jones, Thomas Jones, Tim Jones, Tracey Jones, Ramya Jonnalagadda, Rebecca Jordache, Michele Jordan, Sarah Jordan, Abi Jose, Litty Jose, Louise Jose, Sanal Jose, Anna Joseph, Gigee Joseph, P Aiden Joseph, Rosane Joseph, Sibet Joseph, Dhaara Joshi, Mehul Joshi, Pratichi Joshi, Tushar Joshi, Benz Josiah, Lijo Joy, Tiffany Joyce, Hong Ju, Adriel Ju Wen Kwek, Andrew Judd, Edward Jude, Parminder Judge, Jessica Juhl, Sirisha Jujjavarapu, Mark Juniper, Edmund Juszczak, Deepthi Jyothish, Kasamu Kabiru Dawa, Mark Kacar, Nikhil Kadam, Nicole Kader, Ajai Kailey, Matthew Kain, Gail Kakoullis, Azad Kala Bhushan, Richard J K Kalayi, Roobala Kaliannan Periyasami, Efthymia Kallistrou, Thomas Kalmus Eliasz, Seika Kalsoom, Elisa Kam, 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Robert Laing, Inez Laing-Faiers, Emily Laity, Katharine Lake, Nicki Lakeman, David Lalloo, Fiona Lalloo, Alison Lam, Classy Lam, Fiona Lamb, Lucy Lamb, Thomas Lamb, Oscar Lambert, Pauline Lambert, Claudia Lameirinhas, Mohammed K G Lami, Holly Lamont, Michal Lamparski, Djillali Lamrani, Christine Lanaghan, Ivone Lancona-Malcolm, Geraldine Landers, Martin J Landray, Matthew Lane, Nicholas Lane, Alidih Lang, Stephen Lang, Daniel Langer, Margaret Langley, Charles Langoya, Emma Langridge, Emily Langthorne, Helen Langton, Beatriz Lara, Taiya Large, Lawrencia Naadu Lartey, Samuel Lassa, Anna Last, Scott Latham, Victoria Latham, Afzal Latheef, Larissa Latif, Nang Latt, Carmen Lau, Dawn Lau, Eva Lau, Gonzalez G Laura, Myra Laurenson, Eloise Lavington, Hou Law, Jessica Law, June Law, Kar Y Law, Penny Law, Richard Law, Laura Lawless, Chris Lawrence, Emma Lawrence, Geoffrey Lawrence, Holly M Lawrence, Neil Lawrence, Ryan Lawrie, Louise Lawson, Natalie Lawson, Rod Lawson, Michael Lay, Stephen Laybourne, Christine Laycock, Reina Layug, Maria Lazo, Thi Thao Le, Vietland Le, Amelia Lea, William Lea, Louisa E Leach, Ian Leadbitter, Thomas Leahy, Richard Lean, Lorna Leandro, Darren Leaning, Ruth Leary, Sandra Leason, Marie A Ledingham, Caroline Lee, Emma Lee, Hannah Lee, Irish Lee, Joshua Lee, Judith Lee, Sam Lee, Shannon Lee, Shi Han Lee, Simon Lee, Sindy Lee, Stephanie Lee, Tracey Lee, Xiang Lee, Robyn Lee, Diana Lees, Jennifer Lees, Helen Legge, Julian Leggett, Katie Leigh-Ellis, David Leitch, Nicky Leitch, Eleni Lekoudis, Petula Lemessy, Nicholas Lemoine, Rebecca Lenagh, Katy Leng, Katrina Lennon, Liz Lennon, Beth Leonard, Kelly Leonard, Wen Leong, Nicky Leopold, Oskar Lepiarczyk, Isla Leslie, Eva Noviani Lestari, Eleni Lester, Emma Levell, Chris Levett, Anastasia Levynska, Alice Lewin, Alison Lewis, Christopher Lewis, David Lewis, Dee Lewis, Heather Lewis, Joanne Lewis, Joseph Lewis, Kathryn Lewis, Keir Lewis, Leon Lewis, Mandy Lewis, Marissa Lewis, Nicolas Lewis, Robert Lewis, Catherine Lewis-Clarke, Adam Lewszuk, Penny Lewthwaite, Samantha Ley, Angela Liao, Victoria Licence, David Lieberman, Susan Liebeschuetz, Teresa Light, Nicky Lightfoot, Patrick Lillie, Ashling Lillis, Ben Lim, Carys Lim, Ee T Lim, Ivy Lim, Terence Lim, Wei Shen Lim, Wilson Lim, James Limb, Dipraj Limbu, Usha Limbu, Christian Linares, Dermot Linden, Gabriella Lindergard, Kate Lindley, Charlotte Lindsay, Emily Lindsay, Max Lindsay, Helen Lindsay- Clarke, Mirella Ling, Claire Lingam, Linette Linkson, Thinzar Linn, Mike Linney, Conrad Lippold, George Lipscomb, Karen Lipscomb, Laura Lipskis, Ana Lisboa, Evangeline Lister, Jeff Little, Sam Little, Lucy Littlejohn, Sky Liu, Xuedi Liu, Daniel K Llanera, Rhiannon Llewellyn, Martin Llewelyn, Adam Lloyd, Aimee Lloyd, Arwel Lloyd, Oliver Lloyd, Richard Lloyd, Su Lo, David Loader, Caroline Loan, Livia Lobosco, Lydianne Lock, Sara Lock, Stephen Lock, Angela Locke, Jacqueline Locke, Thomas Locke, Teresa Lockett, Jeorghino Lodge, Krishan 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Infection and Global Health Division, University of St Andrews. School of Medicine, and Group, RECOVERY Collaborative

Subjects
Adult, Male, Hypoxia/etiology, SARS-CoV-2, COVID-19, 3rd-DAS, General Medicine, Adrenal Cortex Hormones/therapeutic use, AC, Dexamethasone/therapeutic use, Hospitals, Oxygen, Treatment Outcome, SDG 3 - Good Health and Well-being, MCP, Humans, Female
Abstract

Background Low-dose corticosteroids have been shown to reduce mortality for patients with COVID-19 requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group. Methods This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (ie, receiving oxygen or with oxygen saturation Findings Between May 25, 2021, and May 13, 2022, 1272 patients with COVID-19 and hypoxia receiving no oxygen (eight [1%]) or simple oxygen only (1264 [99%]) were randomly allocated to receive usual care plus higher dose corticosteroids (659 patients) versus usual care alone (613 patients, of whom 87% received low-dose corticosteroids during the follow-up period). Of those randomly assigned, 745 (59%) were in Asia, 512 (40%) in the UK, and 15 (1%) in Africa. 248 (19%) had diabetes and 769 (60%) were male. Overall, 123 (19%) of 659 patients allocated to higher dose corticosteroids versus 75 (12%) of 613 patients allocated to usual care died within 28 days (rate ratio 1·59 [95% CI 1·20–2·10]; p=0·0012). There was also an excess of pneumonia reported to be due to non-COVID infection (64 cases [10%] vs 37 cases [6%]; absolute difference 3·7% [95% CI 0·7–6·6]) and an increase in hyperglycaemia requiring increased insulin dose (142 [22%] vs 87 [14%]; absolute difference 7·4% [95% CI 3·2–11·5]). Interpretation In patients hospitalised for COVID-19 with clinical hypoxia who required either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared with usual care, which included low-dose corticosteroids. The RECOVERY trial continues to assess the effects of higher dose corticosteroids in patients hospitalised with COVID-19 who require non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Funding UK Research and Innovation (Medical Research Council), National Institute of Health and Care Research, and Wellcome Trust.

Published
2023
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33. Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data.

Author

WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group, Dahal, Prabin, d'Alessandro, Umberto, Dorsey, Grant, Guerin, Philippe J, Nsanzabana, Christian, Price, Ric N, Sibley, Carol H, Stepniewska, Kasia, and Talisuna, Ambrose O

Subjects
WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group, Humans, Plasmodium falciparum, Malaria, Falciparum, Artemisinins, Quinolines, Amodiaquine, Drug Combinations, Antimalarials, Drug Therapy, Combination, Prospective Studies, Middle Aged, Infant, Africa, Africa South of the Sahara, Male, Vector-Borne Diseases, Clinical Research, Prevention, Rare Diseases, Infectious Diseases, Clinical Trials and Supportive Activities, Malaria, 2.2 Factors relating to the physical environment, Infection, General & Internal Medicine, Medical and Health Sciences
Abstract

BackgroundArtemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs).MethodsA literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data.ResultsIn total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P 37.5 °C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine).ConclusionsThe three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

Published
2015

34. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.

Author

WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group, Adjuik, Martin A, Allan, Richard, Anvikar, Anupkumar R, Ashley, Elizabeth A, Ba, Mamadou S, Barennes, Hubert, Barnes, Karen I, Bassat, Quique, Baudin, Elisabeth, Björkman, Anders, Bompart, François, Bonnet, Maryline, Borrmann, Steffen, Brasseur, Philippe, Bukirwa, Hasifa, Checchi, Francesco, Cot, Michel, Dahal, Prabin, D'Alessandro, Umberto, Deloron, Philippe, Desai, Meghna, Diap, Graciela, Djimde, Abdoulaye A, Dorsey, Grant, Doumbo, Ogobara K, Espié, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I, Faucher, Jean-François, Faye, Babacar, Flegg, Jennifer A, Gaye, Oumar, Gething, Peter W, González, Raquel, Grandesso, Francesco, Guerin, Philippe J, Guthmann, Jean-Paul, Hamour, Sally, Hasugian, Armedy Ronny, Hay, Simon I, Humphreys, Georgina S, Jullien, Vincent, Juma, Elizabeth, Kamya, Moses R, Karema, Corine, Kiechel, Jean R, Kremsner, Peter G, Krishna, Sanjeev, Lameyre, Valérie, Ibrahim, Laminou M, Lee, Sue J, Lell, Bertrand, Mårtensson, Andreas, Massougbodji, Achille, Menan, Hervé, Ménard, Didier, Menéndez, Clara, Meremikwu, Martin, Moreira, Clarissa, Nabasumba, Carolyn, Nambozi, Michael, Ndiaye, Jean-Louis, Nikiema, Frederic, Nsanzabana, Christian, Ntoumi, Francine, Ogutu, Bernhards R, Olliaro, Piero, Osorio, Lyda, Ouédraogo, Jean-Bosco, Penali, Louis K, Pene, Mbaye, Pinoges, Loretxu, Piola, Patrice, Price, Ric N, Roper, Cally, Rosenthal, Philip J, Rwagacondo, Claude Emile, Same-Ekobo, Albert, Schramm, Birgit, Seck, Amadou, Sharma, Bhawna, Sibley, Carol Hopkins, Sinou, Véronique, Sirima, Sodiomon B, Smith, Jeffery J, Smithuis, Frank, Somé, Fabrice A, Sow, Doudou, Staedke, Sarah G, Stepniewska, Kasia, Swarthout, Todd D, Sylla, Khadime, Talisuna, Ambrose O, Tarning, Joel, Taylor, Walter RJ, Temu, Emmanuel A, Thwing, Julie I, Tjitra, Emiliana, and Tine, Roger CK

Subjects
WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group, Humans, Malaria, Falciparum, Recurrence, Artemisinins, Amodiaquine, Drug Combinations, Antimalarials, Treatment Outcome, Risk Factors, Dose-Response Relationship, Drug, Middle Aged, Africa, Female, Male, Malaria, Plasmodium falciparum, Drug resistance, Artesunate, Dosing, Efficacy, Falciparum, Dose-Response Relationship, Drug, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundArtesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria.MethodsIndividual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites.ResultsForty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P

Published
2015

35. Large outbreak of Legionnaires' disease and Pontiac fever at a military base

Author

AMBROSE, J, HAMPTON, LM, FLEMING-DUTRA, KE, MARTEN, C, McCLUSKY, C, PERRY, C, CLEMMONS, NA, McCORMIC, Z, PEIK, S, MANCUSO, J, BROWN, E, KOZAK, N, TRAVIS, T, LUCAS, C, FIELDS, B, HICKS, L, and CERSOVSKY, SB

Subjects
Emerging Infectious Diseases, Prevention, Good Health and Well Being, Acute Disease, Adult, Age Distribution, Cohort Studies, Confidence Intervals, Disease Outbreaks, Environmental Exposure, Female, Fever, Humans, Incidence, Legionella pneumophila, Legionellosis, Legionnaires' Disease, Male, Middle Aged, Military Facilities, Military Personnel, Respiratory Tract Infections, Retrospective Studies, Risk Factors, Severity of Illness Index, Sex Distribution, United States, Young Adult, Public Health and Health Services, Epidemiology
Abstract

We investigated a mixed outbreak of Legionnaires' disease (LD) and Pontiac fever (PF) at a military base to identify the outbreak's environmental source as well as known legionellosis risk factors. Base workers with possible legionellosis were interviewed and, if consenting, underwent testing for legionellosis. A retrospective cohort study collected information on occupants of the buildings closest to the outbreak source. We identified 29 confirmed and probable LD and 38 PF cases. All cases were exposed to airborne pathogens from a cooling tower. Occupants of the building closest to the cooling tower were 6·9 [95% confidence interval (CI) 2·2-22·0] and 5·5 (95% CI 2·1-14·5) times more likely to develop LD and PF, respectively, than occupants of the next closest building. Thorough preventive measures and aggressive responses to outbreaks, including searching for PF cases in mixed legionellosis outbreaks, are essential for legionellosis control.

Published
2014

36. Pathways linking regional hyperintensities in the brain and slower gait

Author

Bolandzadeh, Niousha, Liu-Ambrose, Teresa, Aizenstein, Howard, Harris, Tamara, Launer, Lenore, Yaffe, Kristine, Kritchevsky, Stephen B, Newman, Anne, and Rosano, Caterina

Subjects
Health Sciences, Neurosciences, Clinical Research, Aging, Aged, Aged, 80 and over, Body Mass Index, Brain, Chronic Pain, Cognition, Cross-Sectional Studies, Educational Status, Female, Gait, Gait Disorders, Neurologic, Humans, Hypertension, Male, Neural Pathways, Neuropsychological Tests, White Matter, White matter hyperintensities, Mobility, Cognitive function, Executive function, Gait speed, Mediation, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Abstract

ImportanceCerebral white matter hyperintensities (WMHs) are involved in the evolution of impaired mobility and executive functions. Executive functions and mobility are also associated. Thus, WMHs may impair mobility directly, by disrupting mobility-related circuits, or indirectly, by disrupting circuits responsible for executive functions. Understanding the mechanisms underlying impaired mobility in late life will increase our capacity to develop effective interventions.ObjectiveTo identify regional WMHs most related to slower gait and to examine whether these regional WMHs directly impact mobility, or indirectly by executive functions.DesignCross-sectional study. Twenty-one WMH variables (i.e., total WMH volume and WMHs in 20 tracts), gait speed, global cognition (Modified Mini-Mental State Examination; 3MS), and executive functions and processing speed (Digit-Symbol Substitution Test; DSST) were assessed. An L1-L2 regularized regression (i.e., Elastic Net model) identified the WMH variables most related to slower gait. Multivariable linear regression models quantified the association between these WMH variables and gait speed. Formal tests of mediation were also conducted.SettingCommunity-based sample.ParticipantsTwo hundred fifty-three adults (mean age: 83years, 58% women, 41% black).Main outcome measureGait speed.ResultsIn older adults with an average gait speed of 0.91m/sec, total WMH volume, WMHs located in the right anterior thalamic radiation (ATRR) and frontal corpuscallosum (CCF) were most associated with slower gait. There was a >10% slower gait for each standard deviation of WMH in CCF, ATRR or total brain (standardized beta in m/sec [p value]: -0.11 [p=0.046], -0.15 [p=0.007] and -0.14 [p=0.010], respectively). These associations were substantially and significantly attenuated after adjustment for DSST. This effect was stronger for WMH in CCF than for ATRR or total WMH (standardized beta in m/sec [p value]: -0.07 [p=0.190], -0.12 [p=0.024] and -0.10 [p=0.049], respectively). Adjustment for 3MS did not change these associations. The mediation analyses also found that DSST significantly mediated the associations between WMHs and gait speed. Our models were adjusted for age, sex, BMI, quadriceps strength, years of education, standing height, and prevalent hypertension.ConclusionThe impact, direct or indirect, of WMHs on gait speed depended on their location and was mediated by executive function. Thus, multi-faceted interventions targeting executive control functions as well as motor functions, such as balance and strength training, are candidates to the maintenance of mobility across the lifespan.

Published
2014

37. Genetic variation in OPRD1 and the response to treatment for opioid dependence with buprenorphine in European-American females

Author

Clarke, T-K, Crist, RC, Ang, A, Ambrose-Lanci, LM, Lohoff, FW, Saxon, AJ, Ling, W, Hillhouse, MP, Bruce, RD, Woody, G, and Berrettini, WH

Subjects
Prescription Drug Abuse, Genetic Testing, Brain Disorders, Human Genome, Genetics, Neurosciences, Clinical Trials and Supportive Activities, Substance Misuse, Drug Abuse (NIDA only), Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, Buprenorphine, Female, Genetic Variation, Humans, Opioid-Related Disorders, Receptors, Opioid, delta, White People, buprenorphine, females, methadone, opioids, OPRD1, pharmacogenetics, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy
Abstract

Two commonly prescribed treatments for opioid addiction are methadone and buprenorphine. Although these drugs show some efficacy in treating opioid dependence, treatment response varies among individuals. It is likely that genetic factors have a role in determining treatment outcome. This study analyses the pharmacogenetic association of six polymorphisms in OPRD1, the gene encoding the delta-opioid receptor, on treatment outcome in 582 opioid addicted European Americans randomized to either methadone or buprenorphine/naloxone (Suboxone) over the course of a 24-week open-label clinical trial. Treatment outcome was assessed as the number of missed or opioid-positive urine drug screens over the 24 weeks. In the total sample, no single-nucleotide polymorphisms (SNPs) in OPRD1 were significantly associated with treatment outcome in either treatment arm. However, sex-specific analyses revealed two intronic SNPs (rs581111 and rs529520) that predicted treatment outcome in females treated with buprenorphine. Females with the AA or AG genotypes at rs581111 had significantly worse outcomes than those with the GG genotype when treated with buprenorphine (P=0.03, relative risk (RR)=1.67, 95% confidence interval (CI) 1.06-2.1). For rs529520, females with the AA genotype had a significantly worse outcome than those with the CC genotype when (P=0.006, RR=2.15, 95% CI 1.3-2.29). No significant associations were detected in males. These findings suggest that rs581111 and rs52920 may be useful when considering treatment options for female opioid addicts, however, confirmation in an independent sample is warranted.

Published
2014

38. Impact of Vancomycin on sarA-Mediated Biofilm Formation: Role in Persistent Endovascular Infections Due to Methicillin-Resistant Staphylococcus aureus

Author

Abdelhady, Wessam, Bayer, Arnold S, Seidl, Kati, Moormeier, Derek E, Bayles, Kenneth W, Cheung, Ambrose, Yeaman, Michael R, and Xiong, Yan Q

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Microbiology, Clinical Sciences, Medical Microbiology, Prevention, Antimicrobial Resistance, Biodefense, Emerging Infectious Diseases, Infectious Diseases, Vaccine Related, Aetiology, 2.2 Factors relating to the physical environment, 2.1 Biological and endogenous factors, Infection, Animals, Anti-Bacterial Agents, Autolysis, Bacterial Proteins, Biofilms, Endocarditis, Bacterial, Fibronectins, Humans, Methicillin-Resistant Staphylococcus aureus, Microbial Sensitivity Tests, Rabbits, Real-Time Polymerase Chain Reaction, Staphylococcal Infections, Vancomycin, Virulence, sarA, biofilm formation, MRSA endocarditis, Medical and Health Sciences, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundStaphylococcus aureus is the most common cause of endovascular infections. The staphylococcal accessory regulator A locus (sarA) is a major virulence determinant that may potentially impact methicillin-resistant S. aureus (MRSA) persistence in such infections via its influence on biofilm formation.MethodsTwo healthcare-associated MRSA isolates from patients with persistent bacteremia and 2 prototypical community-acquired MRSA strains, as well as their respective isogenic sarA mutants, were studied for in vitro biofilm formation, fibronectin-binding capacity, autolysis, and protease and nuclease activities. These assays were done in the presence or absence of sub-minimum inhibitory concentrations (MICs) of vancomycin. In addition, these strain pairs were compared for intrinsic virulence and responses to vancomycin therapy in experimental infective endocarditis, a prototypical biofilm model.ResultsAll sarA mutants displayed significantly reduced biofilm formation and binding to fibronectin but increased protease production in vitro, compared with their respective parental strains. Interestingly, exposure to sub-MICs of vancomycin significantly promoted biofilm formation and fibronectin-binding in parental strains but not in sarA mutants. In addition, all sarA mutants became exquisitely susceptible to vancomycin therapy, compared with their respective parental strains, in the infective endocarditis model.ConclusionsThese observations suggest that sarA activation is important in persistent MRSA endovascular infection, potentially in the setting of biofilm formation.

Published
2014

39. Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6

Author

Kurt S. Van Horn, Dongju Wang, Daniel Medina-Cleghorn, Peter S. Lee, Clifford Bryant, Chad Altobelli, Priyadarshini Jaishankar, Kevin K. Leung, Raymond A. Ng, Andrew J. Ambrose, Yinyan Tang, Michelle R. Arkin, and Adam R. Renslo

Subjects
Caspase 6, 1.1 Normal biological development and functioning, Apoptosis, General Chemistry, Cysteine Proteinase Inhibitors, Biochemistry, Catalysis, Rare Diseases, Colloid and Surface Chemistry, Underpinning research, Caspases, Chemical Sciences, Humans, Cysteine, Generic health relevance
Abstract

Caspases are a family of cysteine-dependent proteases with important cellular functions in inflammation and apoptosis, while also implicated in human diseases. Classical chemical tools to study caspase functions lack selectivity for specific caspase family members due to highly conserved active sites and catalytic machinery. To overcome this limitation, we targeted a non-catalytic cysteine residue (C264) unique to caspase-6 (C6), an enigmatic and understudied caspase isoform. Starting from disulfide ligands identified in a cysteine trapping screen, we used a structure-informed covalent ligand design to produce potent, irreversible inhibitors (3a) and chemoproteomic probes (13-t) of C6 that exhibit unprecedented selectivity over other caspase family members and high proteome selectivity. This approach and the new tools described will enable rigorous interrogation of the role of caspase-6 in developmental biology and in inflammatory and neurodegenerative diseases.

Published
2023
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40. Taking the "waste" out of "wastewater" for human water security and ecosystem sustainability.

Author

Grant, Stanley B, Saphores, Jean-Daniel, Feldman, David L, Hamilton, Andrew J, Fletcher, Tim D, Cook, Perran LM, Stewardson, Michael, Sanders, Brett F, Levin, Lisa A, Ambrose, Richard F, Deletic, Ana, Brown, Rebekah, Jiang, Sunny C, Rosso, Diego, Cooper, William J, and Marusic, Ivan

Subjects
Humans, Conservation of Natural Resources, Ecosystem, Biodiversity, Fresh Water, Sewage, Water Pollution, Waste Disposal, Fluid, Water Purification, Water Supply, Developed Countries, Developing Countries, Agriculture, Recycling, Drinking Water, Water Quality, Clean Water and Sanitation, General Science & Technology
Abstract

Humans create vast quantities of wastewater through inefficiencies and poor management of water systems. The wasting of water poses sustainability challenges, depletes energy reserves, and undermines human water security and ecosystem health. Here we review emerging approaches for reusing wastewater and minimizing its generation. These complementary options make the most of scarce freshwater resources, serve the varying water needs of both developed and developing countries, and confer a variety of environmental benefits. Their widespread adoption will require changing how freshwater is sourced, used, managed, and priced.

Published
2012

41. A mouse model of post-arthroplasty Staphylococcus aureus joint infection to evaluate in vivo the efficacy of antimicrobial implant coatings.

Author

Bernthal, Nicholas M, Stavrakis, Alexandra I, Billi, Fabrizio, Cho, John S, Kremen, Thomas J, Simon, Scott I, Cheung, Ambrose L, Finerman, Gerald A, Lieberman, Jay R, Adams, John S, and Miller, Lloyd S

Subjects
Joints, Animals, Mice, Inbred C57BL, Humans, Mice, Staphylococcus aureus, Staphylococcal Infections, Joint Diseases, Disease Models, Animal, Postoperative Complications, Rifampin, Minocycline, Anti-Bacterial Agents, Arthroplasty, Prostheses and Implants, Male, Inbred C57BL, Disease Models, Animal, General Science & Technology
Abstract

BackgroundPost-arthroplasty infections represent a devastating complication of total joint replacement surgery, resulting in multiple reoperations, prolonged antibiotic use, extended disability and worse clinical outcomes. As the number of arthroplasties in the U.S. will exceed 3.8 million surgeries per year by 2030, the number of post-arthroplasty infections is projected to increase to over 266,000 infections annually. The treatment of these infections will exhaust healthcare resources and dramatically increase medical costs.Methodology/principal findingsTo evaluate novel preventative therapeutic strategies against post-arthroplasty infections, a mouse model was developed in which a bioluminescent Staphylococcus aureus strain was inoculated into a knee joint containing an orthopaedic implant and advanced in vivo imaging was used to measure the bacterial burden in real-time. Mice inoculated with 5x10(3) and 5x10(4) CFUs developed increased bacterial counts with marked swelling of the affected leg, consistent with an acute joint infection. In contrast, mice inoculated with 5x10(2) CFUs developed a low-grade infection, resembling a more chronic infection. Ex vivo bacterial counts highly correlated with in vivo bioluminescence signals and EGFP-neutrophil fluorescence of LysEGFP mice was used to measure the infection-induced inflammation. Furthermore, biofilm formation on the implants was visualized at 7 and 14 postoperative days by variable-pressure scanning electron microscopy (VP-SEM). Using this model, a minocycline/rifampin-impregnated bioresorbable polymer implant coating was effective in reducing the infection, decreasing inflammation and preventing biofilm formation.Conclusions/significanceTaken together, this mouse model may represent an alternative pre-clinical screening tool to evaluate novel in vivo therapeutic strategies before studies in larger animals and in human subjects. Furthermore, the antibiotic-polymer implant coating evaluated in this study was clinically effective, suggesting the potential for this strategy as a therapeutic intervention to combat post-arthroplasty infections.

Published
2010

42. Monitoring antimalarial safety and tolerability in clinical trials: A case study from Uganda

Author

Staedke, Sarah G, Jagannathan, Prasanna, Yeka, Adoke, Bukirwa, Hasifa, Banek, Kristin, Maiteki-Sebuguzi, Catherine, Clark, Tamara D, Nzarubara, Bridget, Njama-Meya, Denise, Mpimbaza, Arthur, Rosenthal, Philip J, Kamya, Moses R, Wabwire-Mangen, Fred, Dorsey, Grant, and Talisuna, Ambrose O

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Malaria, Vector-Borne Diseases, Infectious Diseases, Orphan Drug, Clinical Trials and Supportive Activities, Rare Diseases, Clinical Research, Patient Safety, 8.4 Research design and methodologies (health services), Evaluation of treatments and therapeutic interventions, Health and social care services research, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Adverse Drug Reaction Reporting Systems, Antimalarials, Artemisinins, Child, Child, Preschool, Drug Therapy, Combination, Humans, Infant, Randomized Controlled Trials as Topic, Treatment Outcome, Uganda, Microbiology, Public Health and Health Services, Tropical Medicine, Medical microbiology, Public health
Abstract

BackgroundNew antimalarial regimens, including artemisinin-based combination therapies (ACTs), have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials.Case descriptionBetween 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity.Discussion and evaluationDespite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported.ConclusionAlthough the World Health Organization has supported the development of pharmacovigilance systems in African countries deploying ACTs, additional guidance on adverse events monitoring in antimalarial clinical trials is needed, similar to the standardized recommendations available for assessment of drug efficacy.

Published
2008

43. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treating uncomplicated malaria: a randomized trial to guide policy in Uganda.

Author

Yeka, Adoke, Dorsey, Grant, Kamya, Moses R, Talisuna, Ambrose, Lugemwa, Myers, Rwakimari, John Bosco, Staedke, Sarah G, Rosenthal, Philip J, Wabwire-Mangen, Fred, and Bukirwa, Hasifa

Subjects
Humans, Malaria, Falciparum, Ethanolamines, Artemisinins, Quinolines, Fluorenes, Antimalarials, Drug Therapy, Combination, Health Policy, Child, Child, Preschool, Infant, Uganda, Artemether, Lumefantrine, Malaria, Falciparum, Drug Therapy, Combination, Preschool, General Science & Technology
Abstract

BackgroundUganda recently adopted artemether-lumefantrine (AL) as the recommended first-line treatment for uncomplicated malaria. However, AL has several limitations, including a twice-daily dosing regimen, recommendation for administration with fatty food, and a high risk of reinfection soon after therapy in high transmission areas. Dihydroartemisinin-piperaquine (DP) is a new alternative artemisinin-based combination therapy that is dosed once daily and has a long post-treatment prophylactic effect. We compared the efficacy and safety of AL with DP in Kanungu, an area of moderate malaria transmission.Methodology/principal findingsPatients aged 6 months to 10 years with uncomplicated falciparum malaria were randomized to therapy and followed for 42 days. Genotyping was used to distinguish recrudescence from new infection. Of 414 patients enrolled, 408 completed follow-up. Compared to patients treated with artemether-lumefantrine, patients treated with dihydroartemisinin-piperaquine had a significantly lower risk of recurrent parasitaemia (33.2% vs. 12.2%; risk difference = 20.9%, 95% CI 13.0-28.8%) but no statistically significant difference in the risk of treatment failure due to recrudescence (5.8% vs. 2.0%; risk difference = 3.8%, 95% CI -0.2-7.8%). Patients treated with dihydroartemisinin-piperaquine also had a lower risk of developing gametocytaemia after therapy (4.2% vs. 10.6%, p = 0.01). Both drugs were safe and well tolerated.Conclusions/significanceDP is highly efficacious, and operationally preferable to AL because of a less intensive dosing schedule and requirements. Dihydroartemisinin-piperaquine should be considered for a role in the antimalarial treatment policy of Uganda.Trial registrationControlled-Trials.com ISRCTN75606663.

Published
2008

45. DNA sensor-associated type I interferon signaling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids

Author

Peter Flood, Aine Fanning, Jerzy A. Woznicki, Tadhg Crowley, Andrea Christopher, Alessandra Vaccaro, Aileen Houston, Sheila McSweeney, Sarah Ross, Aileen Hogan, Elizabeth Brint, Agnieszka Skowyra, Milan Bustamante, Monica Ambrose, Gerard Moloney, John MacSharry, Marie-Louise Hammarström, Margot Hurley, Christine Fitzgibbons, Eamonn M. M. Quigley, Fergus Shanahan, Syed A. Zulquernain, Jane McCarthy, G. Steven Dodson, Karim Dabbagh, Bradford L. McRae, Silvia Melgar, and Ken Nally

Subjects
Inflammasomes, Physiology, Epithelium, Inflammasome, Physiology (medical), NLR Family, Pyrin Domain-Containing 3 Protein, Humans, Janus Kinase Inhibitors, Cell Death, Hepatology, Tumor Necrosis Factor-alpha, Caspase 1, Interleukin-18, Gastroenterology, DNA, Pyrin, Caspase Inhibitors, Nucleotidyltransferases, Antigens, Differentiation, Organoids, DNA-Binding Proteins, Ulcerative colitis, JAK inhibitor, Interferon Type I, Interferon, Colitis, Ulcerative
Abstract

DNA sensor pathways can initiate inflammasome, cell death and type I interferon (IFN) signalling in immune-mediated inflammatory diseases (IMIDs); including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC); by analysing expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n=31), inactive UC (n=31), active UC (n=33) and a UC single cell RNA-Seq dataset. The effects of type I IFN (IFN-β), IFN-γ and TNF-α on gene expression, cytokine production and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLRP3, caspase or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1β/IL-18/CXCL10. The expression of DNA sensor pathway genes - PYHIN family members (AIM2, IFI16, MNDA, PYHIN1), as well as ZBP1, cGAS and DDX41 were increased in active UC and expressed in a cell type restricted pattern. Inflammasome genes (CASP1, IL1B, IL18), type I IFN inducers (STING, TBK1, IRF3), IFNB1 and type I IFN biomarker genes (OAS2, IFIT2, MX2) were also increased in active UC. Co-treatment of organoids with IFN-β or IFN-γ and TNFα increased expression of IFI16, ZBP1, CASP1, cGAS and STING, induced cell death and IL-1β/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC.

Published
2022
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46. Objective Sleep Quality and the Underlying Functional Neural Correlates Among Older Adults with Possible Mild Cognitive Impairment

Author

Chun Liang Hsu, Ryan S. Falck, Daniel Backhouse, Patrick Chan, Elizabeth Dao, Lisanne F. ten Brinke, Brad Manor, and Teresa Liu-Ambrose

Subjects
Brain Mapping, Psychiatry and Mental health, Clinical Psychology, Cross-Sectional Studies, Sleep Quality, General Neuroscience, Humans, Sleep Deprivation, Cognitive Dysfunction, General Medicine, Geriatrics and Gerontology, Aged
Abstract

Background: Poor sleep quality is common among older individuals with mild cognitive impairment (MCI) and may be a consequence of functional alterations in the brain; yet few studies have investigated the underlying neural correlates of actigraphy-measured sleep quality in this cohort. Objective: The objective of this study was to examine the relationship between brain networks and sleep quality measured by actigraphy. Methods: In this cross-sectional analysis, sleep efficiency and sleep fragmentation were estimated using Motionwatch8 (MW8) over a period of 14 days in 36 community-dwelling older adults with possible MCI aged 65–85 years. All 36 participants underwent resting-state functional magnetic resonance imaging (fMRI) scanning. Independent associations between network connectivity and MW8 measures of sleep quality were determined using general linear modeling via FSL. Networks examined included the somatosensory network (SMN), frontoparietal network (FPN), and default mode network (DMN). Results: Across the 36 participants (mean age 71.8 years; SD = 5.2 years), mean Montreal Cognitive Assessment score was 22.5 (SD = 2.7) and Mini-Mental State Examination score was 28.3 (SD = 1.5). Mean sleep efficiency and fragmentation index was 80.1% (SD = 10.0) and 31.8 (SD = 10.4) respectively. Higher sleep fragmentation was significantly correlated with increased connectivity between the SMN and insula, the SMN and posterior cingulate, as well as FPN and primary motor area (FDR-corrected, p

Published
2022
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47. Artemisinin versus nonartemisinin combination therapy for uncomplicated malaria: randomized clinical trials from four sites in Uganda.

Author

Yeka, Adoke, Banek, Kristin, Bakyaita, Nathan, Staedke, Sarah G, Kamya, Moses R, Talisuna, Ambrose, Kironde, Fred, Nsobya, Samuel L, Kilian, Albert, Slater, Madeline, Reingold, Arthur, Rosenthal, Philip J, Wabwire-Mangen, Fred, and Dorsey, Grant

Subjects
Humans, Malaria, Sulfadoxine, Sesquiterpenes, Artemisinins, Pyrimethamine, Amodiaquine, Chloroquine, Drug Combinations, Antimalarials, Treatment Outcome, Drug Therapy, Combination, Risk Factors, Genotype, Child, Preschool, Infant, Uganda, Female, Male, Infections, Drug Therapy, Combination, Child, Preschool, Infection, General & Internal Medicine, Medical and Health Sciences
Abstract

BackgroundDrug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity.Methods and findingsWe enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ) + sulfadoxine-pyrimethamine (SP); amodiaquine (AQ) + SP; or AQ + artesunate (AS). Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed follow-up, of which 1,749 (84%) were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p < 0.01) after AQ + SP or AQ + AS (7%-18% and 4%-12%, respectively). Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection) was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, p < 0.003).ConclusionAQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy. The registration number for this trial is ISRCTN67520427 (http://www.controlled-trials.com/isrctn/trial/|/0/67520427.html).

Published
2005

48. In vivo port-wine stain depth determination with a photoacoustic probe.

Author

Viator, John A, Choi, Bernard, Ambrose, Martin, Spanier, Jerome, and Nelson, J Stuart

Subjects
Skin, Acoustics, Equipment and Supplies, Humans, Melanins, Optics and Photonics, Phantoms, Imaging, Port-Wine Stain, Optical Physics, Electrical and Electronic Engineering, Mechanical Engineering, Optics
Abstract

We have designed a photoacoustic probe for port-wine stain (PWS) depth measurements consisting of optical fibers for laser light delivery and a piezoelectric element for acoustic detection. We characterized the capabilities and limitations of the probe for profiling PWS skin. The probe induced and measured photoacoustic waves in acrylamide tissue phantoms and PWS skin in vivo. The optical properties of the phantoms were chosen to mimic those of PWS skin. We denoised acoustic waves using spline wavelet transforms, then deconvolved with the impulse response of the probe to yield initial subsurface pressure distributions in phantoms and PWS skin. Using the phantoms, we determined that the limit in resolving epidermal and PWS layers was less than 70 microm. In addition, we used the phantoms to determine that the maximum epidermal melanin concentration that allowed detection of PWS was between 13 and 20%. In vivo measurements of PWS skin with different epidermal melanin concentrations correlated with the phantoms. Thus the photoacoustic probe can be used to determine PWS depth for most patients receiving laser therapy.

Published
2003

50. Baseline health-related quality of life predicts falls: a secondary analysis of a randomized controlled trial

Author

Jennifer C. Davis, Chun Liang Hsu, Cheyenne Ghag, Samantha Y. Starkey, Patrizio Jacova, Larry Dian, Naaz Parmar, Kenneth Madden, and Teresa Liu-Ambrose

Subjects
Male, Quality of Life, Public Health, Environmental and Occupational Health, Humans, Female, Exercise, Aged, Exercise Therapy
Abstract

Among older adults, health-related quality of life (HRQoL) and falls are associated. Generic patient-reported outcomes measures (PROMs) assess individual's HRQoL. The role for PROMs, a potential tool for predicting subsequent falls, remains under-explored. Our primary aim was to determine whether a baseline PROMs assessment of HRQoL may be a useful tool for predicting future falls.A secondary analysis of a 12-month randomized clinical trial (RCT) of a home-based exercise program among 344 adults (67% female), aged ≥ 70 years, with ≥ 1 falls in the prior year who were randomized (1:1) to either a home-based exercise program (n = 172) or usual care (n = 172). A negative binomial regression model with total falls count as the dependent variable evaluated the main effect of the independent variable-baseline HRQoL (measured by the Short-Form-6D)-controlling for total exposure time and experiment group (i.e., exercise or usual care) for the total sample. For the usual care group alone, the model controlled for total exposure time.For the total sample, the rate of subsequent total falls was significantly predicted by baseline HRQoL (IRR = 0.044; 95% CI [0.005-0.037]; p = .004). For the usual care group, findings were confirmed with wider confidence intervals and the rate of prospective total falls was significantly predicted by baseline HRQoL (IRR = 0.025; 95% CI [0.001-0.909]; p = .044).These findings suggest the ShortForm-6D should be considered as part of falls prevention screening strategies within a Falls Prevention Clinic setting. Trial Registrations ClinicalTrials.gov Protocol Registration System. Identifier: NCT01029171; URL: https://clinicaltrials.gov/ct2/show/NCT01029171 . Identifier: NCT00323596; URL: https://clinicaltrials.gov/ct2/show/NCT00323596 .

Published
2022
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