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1. Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

Author

Zheng, Sean L., Henry, Albert, Cannie, Douglas, Lee, Michael, Miller, David, McGurk, Kathryn A., Bond, Isabelle, Xu, Xiao, Issa, Hanane, Francis, Catherine, De Marvao, Antonio, Theotokis, Pantazis I., Buchan, Rachel J., Speed, Doug, Abner, Erik, Adams, Lance, Aragam, Krishna G., Ärnlöv, Johan, Raja, Anna Axelsson, Backman, Joshua D., Baksi, John, Barton, Paul J. R., Biddinger, Kiran J., Boersma, Eric, Brandimarto, Jeffrey, Brunak, Søren, Bundgaard, Henning, Carey, David J., Charron, Philippe, Cook, James P., Cook, Stuart A., Denaxas, Spiros, Deleuze, Jean-François, Doney, Alexander S., Elliott, Perry, Erikstrup, Christian, Esko, Tõnu, Farber-Eger, Eric H., Finan, Chris, Garnier, Sophie, Ghouse, Jonas, Giedraitis, Vilmantas, Guðbjartsson, Daniel F., Haggerty, Christopher M., Halliday, Brian P., Helgadottir, Anna, Hemingway, Harry, Hillege, Hans L., Kardys, Isabella, Lind, Lars, Lindgren, Cecilia M., Lowery, Brandon D., Manisty, Charlotte, Margulies, Kenneth B., Moon, James C., Mordi, Ify R., Morley, Michael P., Morris, Andrew D., Morris, Andrew P., Morton, Lori, Noursadeghi, Mahdad, Ostrowski, Sisse R., Owens, Anjali T., Palmer, Colin N. A., Pantazis, Antonis, Pedersen, Ole B. V., Prasad, Sanjay K., Shekhar, Akshay, Smelser, Diane T., Srinivasan, Sundararajan, Stefansson, Kari, Sveinbjörnsson, Garðar, Syrris, Petros, Tammesoo, Mari-Liis, Tayal, Upasana, Teder-Laving, Maris, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Tragante, Vinicius, Trégouët, David-Alexandre, Treibel, Thomas A., Ullum, Henrik, Valdes, Ana M., van Setten, Jessica, van Vugt, Marion, Veluchamy, Abirami, Verschuren, W. M. Monique, Villard, Eric, Yang, Yifan, Asselbergs, Folkert W., Cappola, Thomas P., Dube, Marie-Pierre, Dunn, Michael E., Ellinor, Patrick T., Hingorani, Aroon D., Lang, Chim C., Samani, Nilesh J., Shah, Svati H., Smith, J. Gustav, Vasan, Ramachandran S., O’Regan, Declan P., Holm, Hilma, Noseda, Michela, Wells, Quinn, Ware, James S., and Lumbers, R. Thomas

Published
2024
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5. Gut Microbiome Diversity and Composition Correlates With Time in the Therapeutic Range in Patients on Warfarin Treatment: A Pilot Study

Author

Agosti, Pasquale, Kouraki, Afroditi, Dionisi, Tommaso, Addolorato, Giovanni, D’Innocenzo, Luca, Sorrentino, Silvia, De Maio, Flavio, De Candia, Erica, Blanco-Miguez, Aitor, Bazzani, Davide, Bonadiman, Angela, Tonidandel, Guendalina, Bolzan, Mattia, Gianniello, Francesca, Passamonti, Serena M., Abbattista, Maria, Valdes, Ana M., Bucciarelli, Paolo, Peyvandi, Flora, and Menni, Cristina

Published
2024
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8. How people wake up is associated with previous night's sleep together with physical activity and food intake.

Author

Vallat, Raphael, Berry, Sarah E, Tsereteli, Neli, Capdevila, Joan, Khatib, Haya Al, Valdes, Ana M, Delahanty, Linda M, Drew, David A, Chan, Andrew T, Wolf, Jonathan, Franks, Paul W, Spector, Tim D, and Walker, Matthew P

Subjects
Humans, Exercise, Longitudinal Studies, Prospective Studies, Sleep, Eating, Adult, Sleep Research, Behavioral and Social Science, Clinical Research
Abstract

How people wake up and regain alertness in the hours after sleep is related to how they are sleeping, eating, and exercising. Here, in a prospective longitudinal study of 833 twins and genetically unrelated adults, we demonstrate that how effectively an individual awakens in the hours following sleep is not associated with their genetics, but instead, four independent factors: sleep quantity/quality the night before, physical activity the day prior, a breakfast rich in carbohydrate, and a lower blood glucose response following breakfast. Furthermore, an individual's set-point of daily alertness is related to the quality of their sleep, their positive emotional state, and their age. Together, these findings reveal a set of non-genetic (i.e., not fixed) factors associated with daily alertness that are modifiable.

Published
2022

13. Clinical and Preclinical Evidence for Roles of Soluble Epoxide Hydrolase in Osteoarthritis Knee Pain

Author

Gowler, Peter RW, Turnbull, James, Shahtaheri, Mohsen, Gohir, Sameer, Kelly, Tony, McReynolds, Cindy, Yang, Jun, Jha, Rakesh R, Fernandes, Gwen S, Zhang, Weiya, Doherty, Michael, Walsh, David A, Hammock, Bruce D, Valdes, Ana M, Barrett, David A, and Chapman, Victoria

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Pain Research, Osteoarthritis, Aging, Chronic Pain, Arthritis, Development of treatments and therapeutic interventions, Aetiology, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Musculoskeletal, Animals, Eicosanoids, Epoxide Hydrolases, Humans, Mice, Pain
Abstract

ObjectiveChronic pain due to osteoarthritis (OA) is a major clinical problem, and existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous antiinflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (EH) to dihydroxyeicosatrienoic acids (DHETs). We undertook this study to assess whether soluble EH-driven metabolism of EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment.MethodsPotential associations of chronic knee pain with single-nucleotide polymorphisms (SNPs) in the gene-encoding soluble EH and with circulating levels of EETs and DHETs were investigated in human subjects. A surgically induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of soluble EH by N-[1-(1-oxopropy)-4-piperidinyl]-N'-(trifluoromethoxy)phenyl]-urea (TPPU) on weight-bearing asymmetry, hind paw withdrawal thresholds, joint histology, and circulating concentrations of EETs and DHETs.ResultsIn human subjects with chronic knee pain, 3 pain measures were associated with SNPs of the soluble EH gene EPHX2, and in 2 separate cohorts of subjects, circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviors and decreased circulating levels of 8,9-DHET and 14,15-DHET. EET levels were unchanged by TPPU administration.ConclusionOur novel findings support a role of soluble EH in OA pain and suggest that inhibition of soluble EH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain.

Published
2022

16. Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial

Author

Pande, Ira, Tang, Ting Seng, Tran, Gui, Layton, Alison, Price, Elizabeth, Whittam, Lindsay, Venkatachalam, Srinivasan, Huws, Gwenan, Pratt, Arthur, Reynolds, Nick J, Youngstein, Taryn, Walsh, David A, Joseph, Theresa, Mathew, Rengi, Oikonomou, Stamatios, Gwynne, Catherine, Crowder, Rory, Saravanan, Vadivelu, Mustafa, Alaa, Tacu, Cristina, George, Emmanuel, Batty, Thomas, Soni, Anushka, Horton, Sarah, Gaffney, Karl, Gullick, Nicola, Lapin, Agnieszka, Bingham, Sarah, Madan, Ayesha, Holroyd, Chris, Lwin, May, Khalid, Salema, Green, Mike, Hunt, Laura, Alcorn, Nicola, Ellis, Rob, Hider, Samantha, Hassan, Ala, Douglas, Karen, Ho, Gen Nen, Levasseur, Kirsty, Pradeep, John, Rhys-Dillon, Ceril, Jones, Catrin, Abhishek, Abhishek, Peckham, Nicholas, Pade, Corinna, Gibbons, Joseph M, Cureton, Lucy, Francis, Anne, Barber, Vicki, Williams, Jennifer A E, Appelbe, Duncan, Eldridge, Lucy, Julier, Patrick, Altmann, Daniel M, Bluett, James, Brooks, Tim, Coates, Laura C, Rombach, Ines, Semper, Amanda, Otter, Ashley, Valdes, Ana M, Nguyen-Van-Tam, Jonathan S, Williams, Hywel C, Boyton, Rosemary J, McKnight, Áine, and Cook, Jonathan A

Published
2024
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23. The secondary bile acid isoursodeoxycholate correlates with post-prandial lipemia, inflammation, and appetite and changes post-bariatric surgery

Author

Louca, Panayiotis, Meijnikman, Abraham S., Nogal, Ana, Asnicar, Francesco, Attaye, Ilias, Vijay, Amrita, Kouraki, Afroditi, Visconti, Alessia, Wong, Kari, Berry, Sarah E., Leeming, Emily R., Mompeo, Olatz, Tettamanzi, Francesca, Baleanu, Andrei-Florin, Falchi, Mario, Hadjigeorgiou, George, Wolf, Jonathan, Acherman, Yair I.Z., Van de Laar, Arnold W., Gerdes, Victor E.A., Michelotti, Gregory A., Franks, Paul W., Segata, Nicola, Mangino, Massimo, Spector, Tim D., Bulsiewicz, William J., Nieuwdorp, Max, Valdes, Ana M., and Menni, Cristina

Published
2023
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26. Omega-3 Fatty Acid-Derived Resolvin D2 Regulates Human Placental Vascular Smooth Muscle and Extravillous Trophoblast Activities.

Author

Ulu, Arzu, Sahoo, Prakash K, Yuil-Valdes, Ana G, Mukherjee, Maheswari, Van Ormer, Matthew, Muthuraj, Philma Glora, Thompson, Maranda, Anderson Berry, Ann, Hanson, Corrine K, Natarajan, Sathish Kumar, and Nordgren, Tara M

Subjects
Muscle, Smooth, Vascular, Cells, Cultured, Myocytes, Smooth Muscle, Trophoblasts, Placenta, Humans, Fatty Acids, Omega-3, Docosahexaenoic Acids, Receptors, G-Protein-Coupled, Maternal Age, Gene Expression Regulation, Pregnancy, Adult, Female, Young Adult, Hep G2 Cells, GPR18, Resolvin D2, delivery, inflammation, omega-3 fatty acids, placenta, specialized pro-resolving mediators, trophoblasts, Cells, Cultured, Fatty Acids, Omega-3, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Receptors, G-Protein-Coupled, Other Chemical Sciences, Genetics, Other Biological Sciences, Chemical Physics
Abstract

Omega-3 fatty acids are important to pregnancy and neonatal development and health. One mechanism by which omega-3 fatty acids exert their protective effects is through serving as substrates for the generation of specialized pro-resolving lipid mediators (SPM) that potently limit and resolve inflammatory processes. We recently identified that SPM levels are increased in maternal blood at delivery as compared to umbilical cord blood, suggesting the placenta as a potential site of action for maternal SPM. To explore this hypothesis, we obtained human placental samples and stained for the SPM resolvin D2 (RvD2) receptor GPR18 via immunohistochemistry. In so doing, we identified GPR18 expression in placental vascular smooth muscle and extravillous trophoblasts of the placental tissues. Using in vitro culturing, we confirmed expression of GPR18 in these cell types and further identified that stimulation with RvD2 led to significantly altered responsiveness (cytoskeletal changes and pro-inflammatory cytokine production) to lipopolysaccharide inflammatory stimulation in human umbilical artery smooth muscle cells and placental trophoblasts. Taken together, these findings establish a role for SPM actions in human placental tissue.

Published
2019

27. Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial

Author

Pande, Ira, Seng Tang, Ting, Tran, Gui, Layton, Alison, Price, Elizabeth, Whittam, Lindsay, Venkatachalam, Srinivasan, Hawarden, Ashley, Huws, Gwenan, Pratt, Arthur, Reynolds, Nick J, Walsh, David, Joseph, Theresa, Mathew, Rengi, Oikonomou, Stamatios, Gwynne, Catherine, Crowder, Rory, Saravanan, Vadivelu, Mustafa, Alaa, Tacu, Cristina, Batty, Thomas, George, Emmanuel, Soni, Anushka, Horton, Sarah, Madan, Ayesha, Gaffney, Karl, Lapin, Agnieszka, Bingham, Sarah, Levell, Nick, Lim, Edwin, Gullick, Nicola, Holroyd, Chris, Khalid, Salema, Lwin, May, Green, Mike, Hunt, Laura, Alcorn, Nicola, Ellis, Rob, Hider, Samantha, Hassan, Alaa, Youngstein, Taryn, Douglas, Karen, Ho, Gen Nen, Levasseur, Kirsty, Treacy, Sara, Cheila, Myrto, Pradeep, John, Rhys-Dillon, Ceril, Jones, Catrin, Abhishek, Abhishek, Boyton, Rosemary J, Peckham, Nicholas, McKnight, Áine, Coates, Laura C, Bluett, James, Barber, Vicki, Cureton, Lucy, Francis, Anne, Appelbe, Duncan, Eldridge, Lucy, Julier, Patrick, Valdes, Ana M, Brooks, Tim, Rombach, Ines, Altmann, Daniel M, Nguyen-Van-Tam, Jonathan S, Williams, Hywel C, and Cook, Jonathan A

Published
2022
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28. Perspective: Leveraging the Gut Microbiota to Predict Personalized Responses to Dietary, Prebiotic, and Probiotic Interventions

Author

Gibbons, Sean M, Gurry, Thomas, Lampe, Johanna W, Chakrabarti, Anirikh, Dam, Veerle, Everard, Amandine, Goas, Almudena, Gross, Gabriele, Kleerebezem, Michiel, Lane, Jonathan, Maukonen, Johanna, Penna, Ana Lucia Barretto, Pot, Bruno, Valdes, Ana M, Walton, Gemma, Weiss, Adrienne, Zanzer, Yoghatama Cindya, Venlet, Naomi V, and Miani, Michela

Published
2022
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31. Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study

Author

Menni, Cristina, Valdes, Ana M, Polidori, Lorenzo, Antonelli, Michela, Penamakuri, Satya, Nogal, Ana, Louca, Panayiotis, May, Anna, Figueiredo, Jane C, Hu, Christina, Molteni, Erika, Canas, Liane, Österdahl, Marc F, Modat, Marc, Sudre, Carole H, Fox, Ben, Hammers, Alexander, Wolf, Jonathan, Capdevila, Joan, Chan, Andrew T, David, Sean P, Steves, Claire J, Ourselin, Sebastien, and Spector, Tim D

Published
2022
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32. Association of serum biomarkers with radiographic knee osteoarthritis, knee pain and function in a young, male, trauma-exposed population – Findings from the ADVANCE study.

Author

O'Sullivan, Oliver, Stocks, Joanne, Schofield, Susie, Bilzon, James, Boos, Christopher J., Bull, Anthony M.J., Fear, Nicola T., Watt, Fiona E., Bennett, Alexander N., Kluzek, Stefan, and Valdes, Ana M.

Abstract

The ArmeD SerVices TrAuma RehabilitatioN OutComE (ADVANCE) study is investigating long-term combat-injury outcomes; this sub-study aims to understand the association of osteoarthritis (OA) biomarkers with knee radiographic OA (rOA), pain and function in this high-risk population for post-traumatic OA. ADVANCE compares combat-injured participants with age, rank, deployment and job-role frequency-matched uninjured participants. Post-injury immunoassay-measured serum biomarkers, knee radiographs, Knee Injury and Osteoarthritis Outcome Scale, and six-minute walk tests are reported. The primary analysis, adjusted for age, body mass, socioeconomic status, and ethnicity, was to determine any differences in biomarkers between those with/without combat injury, rOA and pain. Secondary analyses were performed to compare post-traumatic/idiopathic OA, painful/painfree rOA and injury patterns. A total of 1145 male participants were recruited, aged 34.1 ± 5.4, 8.9 ± 2.2 years post-injury (n = 579 trauma-exposed, of which, traumatic-amputation n = 161) or deployment (n = 566 matched). Cartilage oligomeric matrix protein (COMP) was significantly higher in the combat-injured group compared to uninjured (p = 0.01). Notably, COMP was significantly lower in the traumatic-amputation group compared to non-amputees (p < 0.001), decreasing relative to number of amputations (p < 0.001). Leptin was higher (p = 0.005) and adiponectin lower (p = 0.017) in those with v without knee pain, associated with an increased risk of 22% and 17% for pain, and 46% and 34% for painful rOA, respectively. There were no significant differences between trauma-exposed and unexposed participants with rOA. The most notable findings of this large, unique study are the similarities between those with rOA regardless of trauma-exposure, the injury-pattern and traumatic-amputation-associated differences in COMP, and the relationship between adipokines and pain. [ABSTRACT FROM AUTHOR]

Published
2024
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33. Supplementation with Citrus Low-Methoxy Pectin Reduces Levels of Inflammation and Anxiety in Healthy Volunteers: A Pilot Controlled Dietary Intervention Study.

Author

Vijay, Amrita, Kelly, Anthony, Miller, Suzanne, Marshall, Melanie, Alonso, Althea, Kouraki, Afroditi, Probert, Catherine, Simpson, Elizabeth J., and Valdes, Ana M.

Abstract

Background/Objective: Although low-methoxy (LM) pectin (polysaccharides extracted from citrus peels) can reduce inflammation by binding to and inhibiting the TLR-2 pathway in animal models and in vitro studies, the anti-inflammatory effects of LM pectin in humans and mood have not been explored to date. The purpose of this study is to assess the role of dietary supplementation with LM pectin in healthy volunteers on inflammatory markers and on mood, specifically anxiety and depression. Methods: We carried out a 4-week dietary intervention with LM citrus pectin on healthy volunteers (N = 14, age 40 ± 16 y, BMI 24.7 ± 3.0 kg/m2, sex F 57%) comparing the effects of daily supplementation with 20 g of LM citrus pectin versus 10 g of maltodextrin as the control (N = 15 age 43.2 ± 11 y, BMI 25.18 ± 2.0 kg/m2, sex F 66%). The effects on mood and inflammation were also tested with LM pectin at 5 g, 10 g and 15 g (2 weeks each) in an independent cohort of n = 15 healthy volunteers (age 36 ± 21 y, BMI 23.5 ± 2.4 kg/m2, sex F 80%). We assessed serum levels of TNF-alpha (downstream from TLR-2 activation), IL-1 beta, IL-6, IL-10, INF-gamma, CRP, zonulin and TLR-2 concentration which were measured using ELISA in blood samples collected at both the baseline and follow-up visits. Validated measures of anxiety and depression were collected at baseline and follow-up. Results: Supplementation with 20 g of LM pectin resulted in decreases in the pro-inflammatory markers TNF-alpha, IL-1 beta, IL-6 and INF-gamma (all p < 0.05) and an increase in anti-inflammatory marker IL-10 (p = 0.01) at the end of the 4 weeks. No such effects were observed in the control group. In addition, a significant drop in anxiety scores (from 8.38 to 4.46, p < 0.006) was found with the 20 g/day intervention but not in the control arm. In the dose–response study, anti-inflammatory effects were seen only at 15 g for TNFα (p < 0.003) and a suggestive increase in IL-10 (p = 0.08), alongside a drop in TLR-2 (p < 0.027). No significant anti-inflammatory effects were observed at 5 g and 10 g doses of LM pectin supplementation. Significant dose-dependent drops in both anxiety and depression scores were found with 10 g (p < 0.001) and 15 g per day (p < 0.0002). Conclusions: The current study identifies anxiety-reducing and anti-inflammatory effects of supplementation with 15 g/day LM pectin in healthy humans. Further research is needed to elucidate the precise mechanism and to validate the efficient dose and minimum duration of supplementation. [ABSTRACT FROM AUTHOR]

Published
2024
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36. Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2

Author

Swadling, Leo, Diniz, Mariana O., Schmidt, Nathalie M., Amin, Oliver E., Chandran, Aneesh, Shaw, Emily, Pade, Corinna, Gibbons, Joseph M., Le Bert, Nina, Tan, Anthony T., Jeffery-Smith, Anna, Tan, Cedric C. S., Tham, Christine Y. L., Kucykowicz, Stephanie, Aidoo-Micah, Gloryanne, Rosenheim, Joshua, Davies, Jessica, Johnson, Marina, Jensen, Melanie P., Joy, George, McCoy, Laura E., Valdes, Ana M., Chain, Benjamin M., Goldblatt, David, Altmann, Daniel M., Boyton, Rosemary J., Manisty, Charlotte, Treibel, Thomas A., Moon, James C., van Dorp, Lucy, Balloux, Francois, McKnight, Áine, Noursadeghi, Mahdad, Bertoletti, Antonio, and Maini, Mala K.

Published
2022
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37. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Jiang, Xia, O’Reilly, Paul F, Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A, Albanes, Demetrius, Lutsey, Pamela L, Yao, Lu, Tang, Weihong, Econs, Michael J, Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I, Michos, Erin D, Boerwinkle, Eric, Weinstein, Stephanie J, Freedman, Neal D, Huang, Wen-Yi, Van Schoor, Natasja M, van der Velde, Nathalie, Groot, Lisette CPGM de, Enneman, Anke, Cupples, L Adrienne, Booth, Sarah L, Vasan, Ramachandran S, Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G, Shea, M Kyla, Houston, Denise K, Kritchevsky, Stephen B, Liu, Yongmei, Lohman, Kurt K, Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E, März, Winfried, de Boer, Ian H, Wood, Alexis C, Rotter, Jerome I, Rich, Stephen S, Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K, Wilson, James F, Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M Carola, Uitterlinden, Andre G, Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M, Timofeeva, Maria, Dunlop, Malcolm G, Valdes, Ana M, Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T, Mikkilä, Vera, Ikram, M Arfan, Sattar, Naveed, Jukema, J Wouter, Wareham, Nicholas J, Langenberg, Claudia, Forouhi, Nita G, Gundersen, Thomas E, Khaw, Kay-Tee, Butterworth, Adam S, Danesh, John, and Spector, Timothy

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Amidohydrolases, Autoimmune Diseases, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Vesicular Transport Proteins, Vitamin D, White People
Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Published
2018

41. Effects of a personalized nutrition program on cardiometabolic health: a randomized controlled trial

Author

Bermingham, Kate M., primary, Linenberg, Inbar, additional, Polidori, Lorenzo, additional, Asnicar, Francesco, additional, Arrè, Alberto, additional, Wolf, Jonathan, additional, Badri, Fatema, additional, Bernard, Hannah, additional, Capdevila, Joan, additional, Bulsiewicz, William J., additional, Gardner, Christopher D., additional, Ordovas, Jose M., additional, Davies, Richard, additional, Hadjigeorgiou, George, additional, Hall, Wendy L., additional, Delahanty, Linda M., additional, Valdes, Ana M., additional, Segata, Nicola, additional, Spector, Tim D., additional, and Berry, Sarah E., additional

Published
2024
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44. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study

Author

Menni, Cristina, Klaser, Kerstin, May, Anna, Polidori, Lorenzo, Capdevila, Joan, Louca, Panayiotis, Sudre, Carole H, Nguyen, Long H, Drew, David A, Merino, Jordi, Hu, Christina, Selvachandran, Somesh, Antonelli, Michela, Murray, Benjamin, Canas, Liane S, Molteni, Erika, Graham, Mark S, Modat, Marc, Joshi, Amit D, Mangino, Massimo, Hammers, Alexander, Goodman, Anna L, Chan, Andrew T, Wolf, Jonathan, Steves, Claire J, Valdes, Ana M, Ourselin, Sebastien, and Spector, Tim D

Published
2021
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45. Longitudinal assessment of symptoms and risk of SARS-CoV-2 infection in healthcare workers across 5 hospitals to understand ethnic differences in infection risk.

Author

Valdes, Ana M., Moon, James C., Vijay, Amrita, Chaturvedi, Nish, Norrish, Alan, Ikram, Adeel, Craxford, Simon, Cusin, Lola M.L., Nightingale, Jessica, Semper, Amanda, Brooks, Timothy, McKnight, Aine, Kurdi, Hibba, Menni, Cristina, Tighe, Patrick, Noursadeghi, Mahdad, Aithal, Guruprasad, Treibel, Thomas A., Ollivere, Benjamin J., and Manisty, Charlotte

Published
2021
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47. TareApp: Planificador de tareas escolares para personas con dificultades de aprendizaje

Author

Francisco Gilmartín, Virginia, Hervás Ballesteros, Raquel, Bravo Fairen, Lucas, Calvo Martínez, Carlos, Martínez Valdes, Ana María, Rodríguez Prieto, Clara, Sierra Alonso, Jorge, Francisco Gilmartín, Virginia, Hervás Ballesteros, Raquel, Bravo Fairen, Lucas, Calvo Martínez, Carlos, Martínez Valdes, Ana María, Rodríguez Prieto, Clara, and Sierra Alonso, Jorge

Abstract

Aunque las tecnologías digitales han transformado la educación, aún hay un vacío en cuanto a herramientas que atiendan específicamente las necesidades de los estudiantes con dificultades de aprendizaje en términos de organización y planificación. Este TFG se enfoca en el desarrollo de un planificador de tareas destinado a abordar estas dificultades en niños en edad escolar. En el análisis de aplicaciones existentes relacionadas, se identificaron varias herramientas diseñadas para abordar las dificultades de organización y planificación en niños con dificultades de aprendizaje. Estas aplicaciones comparten características comunes como la personalización de tareas, la inclusión de imágenes para facilitar la comprensión, la sincronización en múltiples dispositivos y el uso de elementos entretenidos para aumentar la motivación, pero carecen de la adaptabilidad necesaria para satisfacer las preferencias individuales de los usuarios. Para abordar la problemática de los alumnos con dificultades de aprendizaje, hemos desarrollado una aplicación completa y adaptable. Esta aplicación permite ajustar el formato visual según las preferencias individuales y facilita la gestión de tareas de manera sencilla e intuitiva. Para crear esta aplicación, primero, realizamos una captura de requisitos entrevistando a 12 personas en los centros CEIP Príncipe Felipe y el Colegio Zola Las Rozas. Entre los entrevistados se encontraban cinco profesionales (un especialista de Audición y Lenguaje y 4 profesores de Primaria, Secundaria y Bachillerato), tres alumnos con dificultades de aprendizaje y cuatro familiares de los alumnos entrevistados. Estas entrevistas nos permitieron comprender mejor las necesidades y desafíos a los que se enfrentan las personas con dificultades de aprendizaje a la hora de organizar y planificar sus tareas. Posteriormente, diseñamos la aplicación en dos fases: en una primera fase hicimos un diseño competitivo en el que cada uno de los integrantes del grupo hicimos un p

Published
2024

49. Characterization of Immune Infiltrate Along the Leading Edge of Differentiated Thyroid Cancer.

Author

Kotwal, Anupam, Vance, Krysten, Hajric, Kemal, Yuil-Valdes, Ana, Swanson, Benjamin, Martinez Duarte, Ernesto, Shats, Oleg, Hollingsworth, Michael, Band, Hamid, and Goldner, Whitney

Subjects
REGULATORY T cells, BIOMARKERS, IMMUNE checkpoint proteins, TUMOR-infiltrating immune cells, PROGNOSIS, THYROID cancer
Abstract

Background: Although the impact of tumor-immune infiltrate has been reported on differentiated thyroid cancer (DTC) behavior, the expression of immune checkpoints [programmed cell death protein 1 (PD-1) and its ligand (PD-L1)] alone has not been able to predict response to immunotherapies. We aimed to identify tumor-infiltrating immune cells and checkpoints associated with DTC. Methods: We performed multiplex immunofluorescence on deparaffinized thyroid tissue collected at thyroidectomy from 17 adults with DTC to characterize the tumor immune microenvironment for leukocytes (CD45+), T cells (CD3+), T regulatory cells (Tregs) (CD3+FOXP3+), CD4+ T cells (CD3+CD4+), CD8+ T cells (CD3+CD8+), macrophages (CD68+), M2 macrophages (CD68+CD163+), M1 Macrophages (CD68+ inducible nitric oxide synthase [iNOS]+), and immune checkpoints PD-1 and PD-L1. We compared the mean percentage expression of immune markers between tumor and adjacent thyroid tissue from the same patient by paired t-test and performed spatial analysis along the tumor's leading edge. Results: Immune checkpoints PD-1 and PD-L1 showed a significant increase in expression intratumorally as compared to adjacent thyroid tissue (p < 0.05). A higher trend for M2 macrophages was observed intratumorally compared to adjacent tissue. Along the leading edge, PD-L1 expression correlated negatively with CD45 and positively with CD163 intratumorally. On exploratory analysis, there was a nonsignificant trend for higher FOXP3 but less CD8 and iNOS expression in tumor from DTC with (n = 3) versus without distant metastases (n = 14). There was a nonsignificant trend for higher CD58 and iNOS expression in DTC with (n = 7) than without thyroiditis (n = 10). Conclusions: Higher tumoral PD-1 and PD-L1 expression indicate their role in DTC occurrence. A trend for more Tregs and M2 macrophages but less M1 macrophages intratumorally in patients with distant metastatic DTC, suggests their potential role as prognostic biomarkers. Future studies with larger sample sizes are needed to compare various clinicopathologic severities to harness tumor microenvironment for cancer prognostication and therapy. [ABSTRACT FROM AUTHOR]

Published
2024
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50. Thoracic SMARCA4-Deficient Undifferentiated Tumors With Unusual Presentations: A Case Series.

Author

Helmink, Austin J., Alshomrani, Ahmad, Lauer, Scott R., and Yuil-Valdes, Ana

Abstract

Context: Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently described aggressive neoplasm of young smokers defined by SMARCA4 inactivating mutations and characterized by cells with rhabdoid morphology, high mitotic activity, and abundant necrosis. Objective: Describe and compare 3 unusual presentations of SMARCA4-UT in older adults, including one presenting as a metastatic lesion mimicking a primary bone sarcoma. Discuss the molecular characteristics of SMARCA4-UT and their relationship to nonsmall-cell lung carcinomas with SMARCA4. Design: Three patients with SMARCA4-UTs were identified utilizing a natural language search in CoPath. hematoxylin and eosin sections from all patients as well as Papanicolaou-stained slides and Diff-Quik-stained slides for the first patient were examined. A broad range of immunostains, including BRG1/SMARCA4, were evaluated. Molecular testing was performed via next-generation sequencing. Results: The 3 patients were aged 58, 70, and 70 years. All had a significant smoking history. The first patient presented with an iliac bone mass and mediastinal lymphadenopathy, the second with mediastinal adenopathy, and the third with a paratracheal mass. All 3 tumors showed a diffuse proliferation of pleomorphic, rhabdoid cells with high mitotic activity and tumor necrosis. SMARCA4 was lost in all 3 tumors by immunohistochemistry. Molecular testing revealed SMARCA4 alterations in the first 2. Conclusions: Thoracic SMARCA4-UT should be considered in the differential diagnosis of pleomorphic rhabdoid tumors in older adults with a smoking history. Although most present as lung and/or mediastinal masses, they may occasionally present as a metastasis and mimic an undifferentiated sarcoma, representing a potential diagnostic pitfall. [ABSTRACT FROM AUTHOR]

Published
2024
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