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9,894 results on '"Goldstein, David"'

104. The Plumes and Atmosphere of Io

Author

de Pater, Imke, Goldstein, David, Lellouch, Emmanuel, Shore, Steven N., Series Editor, Lopes, Rosaly M. C., editor, de Kleer, Katherine, editor, and Tuttle Keane, James, editor

Published
2023
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105. Hormonal intervention for the treatment of veterans with COVID-19 requiring hospitalization (HITCH): a multicenter, phase 2 randomized controlled trial of best supportive care vs best supportive care plus degarelix: study protocol for a randomized controlled trial

Author

Nickols, Nicholas G, Goetz, Matthew B, Graber, Christopher J, Bhattacharya, Debika, Soo Hoo, Guy, Might, Matthew, Goldstein, David B, Wang, Xinchen, Ramoni, Rachel, Myrie, Kenute, Tran, Samantha, Ghayouri, Leila, Tsai, Sonny, Geelhoed, Michelle, Makarov, Danil, Becker, Daniel J, Tsay, Jun-Chieh, Diamond, Melissa, George, Asha, Al-Ajam, Mohammad, Belligund, Pooja, Montgomery, R Bruce, Mostaghel, Elahe A, Sulpizio, Carlie, Mi, Zhibao, Dematt, Ellen, Tadalan, Joseph, Norman, Leslie E, Briones, Daniel, Clise, Christina E, Taylor, Zachary W, Huminik, Jeffrey R, Biswas, Kousick, and Rettig, Matthew B

Subjects
Clinical Trials and Supportive Activities, Cancer, Lung, Infectious Diseases, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, COVID-19, Clinical Trials, Phase II as Topic, Hospitalization, Humans, Male, Multicenter Studies as Topic, Oligopeptides, Randomized Controlled Trials as Topic, SARS-CoV-2, Treatment Outcome, Veterans, TMPRSS2, Androgen receptor, Androgen suppression, Coronavirus, Hormone therapy, Anti-androgen, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology, General & Internal Medicine
Abstract

BackgroundTherapeutic targeting of host-cell factors required for SARS-CoV-2 entry is an alternative strategy to ameliorate COVID-19 severity. SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface protease. Pre-clinical and correlative data in humans suggest that anti-androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium. Accordingly, we hypothesize that therapeutic targeting of androgen receptor signaling via degarelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, will suppress COVID-19 infection and ameliorate symptom severity.MethodsThis is a randomized phase 2, placebo-controlled, double-blind clinical trial in 198 patients to compare efficacy of degarelix plus best supportive care versus placebo plus best supportive care on improving the clinical outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled patients must have documented infection with SARS-CoV-2 based on a positive reverse transcriptase polymerase chain reaction result performed on a nasopharyngeal swab and have a severity of illness of level 3-5 (hospitalized but not requiring invasive mechanical ventilation). Patients stratified by age, history of hypertension, and severity are centrally randomized 2:1 (degarelix: placebo). The composite primary endpoint is mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at 15 after randomization. Important secondary endpoints include time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a normal temperature, and the maximum severity of COVID-19 illness. Exploratory analyses aim to assess the association of cytokines, viral load, and various comorbidities with outcome. In addition, TMPRSS2 expression in target tissue and development of anti-viral antibodies will also be investigated.DiscussionIn this trial, we repurpose the FDA approved LHRH antagonist degarelix, commonly used for prostate cancer, to suppress TMPRSS2, a host cell surface protease required for SARS-CoV-2 cell entry. The objective is to determine if temporary androgen suppression with a single dose of degarelix improves the clinical outcomes of patients hospitalized due to COVID-19.Trial registrationClinicalTrials.gov NCT04397718. Registered on May 21, 2020.

Published
2021

107. Improving accuracy in nodal staging of oral cancer: Proposal of a new system

Author

Subramaniam, Narayana, Heller, Gillian, Clark, Jonathan Robert, Gupta, Ruta, Goldstein, David, de Almeida, John R., Hosni, Ali, Balasubramanian, Deepak, Thankappan, Krishnakumar, Iyer, Subramania, Batstone, Martin, Iyer, N. Gopal, Smee, Robert I., Chandrasekhar, Naveen Hedne, Pillai, Vijay, Shetty, Vivek, Rangappa, Vidyabhushan, Veness, Michael, and Low, Tsu-Hui (Hubert)

Published
2024
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108. Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections

Author

Borras, Silvia, Clark, Caroline, Dean, John, Miedzybrodzka, Zosia, Ross, Alison, Tennant, Stephen, Dabir, Tabib, Donnelly, Deirdre, Humphreys, Mervyn, Magee, Alex, McConnell, Vivienne, McKee, Shane, McNerlan, Susan, Morrison, Patrick J., Rea, Gillian, Stewart, Fiona, Cole, Trevor, Cooper, Nicola, Cooper-Charles, Lisa, Cox, Helen, Islam, Lily, Jarvis, Joanna, Keelagher, Rebecca, Lim, Derek, McMullan, Dominic, Morton, Jenny, Naik, Swati, O’Driscoll, Mary, Ong, Kai-Ren, Osio, Deborah, Ragge, Nicola, Turton, Sarah, Vogt, Julie, Williams, Denise, Bodek, Simon, Donaldson, Alan, Hills, Alison, Low, Karen, Newbury-Ecob, Ruth, Norman, Andrew M., Roberts, Eileen, Scurr, Ingrid, Smithson, Sarah, Tooley, Madeleine, Abbs, Steve, Armstrong, Ruth, Dunn, Carolyn, Holden, Simon, Park, Soo-Mi, Paterson, Joan, Raymond, Lucy, Reid, Evan, Sandford, Richard, Simonic, Ingrid, Tischkowitz, Marc, Woods, Geoff, Bradley, Lisa, Comerford, Joanne, Green, Andrew, Lynch, Sally, McQuaid, Shirley, Mullaney, Brendan, Berg, Jonathan, Goudie, David, Mavrak, Eleni, McLean, Joanne, McWilliam, Catherine, Reavey, Eleanor, Azam, Tara, Cleary, Elaine, Jackson, Andrew, Lam, Wayne, Lampe, Anne, Moore, David, Porteous, Mary, Baple, Emma, Baptista, Júlia, Brewer, Carole, Castle, Bruce, Kivuva, Emma, Owens, Martina, Rankin, Julia, Shaw-Smith, Charles, Turner, Claire, Turnpenny, Peter, Tysoe, Carolyn, Bradley, Therese, Davidson, Rosemarie, Gardiner, Carol, Joss, Shelagh, Kinning, Esther, Longman, Cheryl, McGowan, Ruth, Murday, Victoria, Pilz, Daniela, Tobias, Edward, Whiteford, Margo, Williams, Nicola, Barnicoat, Angela, Clement, Emma, Faravelli, Francesca, Hurst, Jane, Jenkins, Lucy, Jones, Wendy, Ajith Kumar, V.K., Lees, Melissa, Loughlin, Sam, Male, Alison, Morrogh, Deborah, Rosser, Elisabeth, Scott, Richard, Wilson, Louise, Beleza, Ana, Deshpande, Charu, Flinter, Frances, Holder, Muriel, Irving, Melita, Izatt, Louise, Josifova, Dragana, Mohammed, Shehla, Molenda, Aneta, Robert, Leema, Roworth, Wendy, Ruddy, Deborah, Ryten, Mina, Yau, Shu, Bennett, Christopher, Blyth, Moira, Campbell, Jennifer, Coates, Andrea, Dobbie, Angus, Hewitt, Sarah, Hobson, Emma, Jackson, Eilidh, Jewell, Rosalyn, Kraus, Alison, Prescott, Katrina, Sheridan, Eamonn, Thomson, Jenny, Bradshaw, Kirsty, Dixit, Abhijit, Eason, Jacqueline, Haines, Rebecca, Harrison, Rachel, Mutch, Stacey, Sarkar, Ajoy, Searle, Claire, Shannon, Nora, Sharif, Abid, Suri, Mohnish, Vasudevan, Pradeep, Canham, Natalie, Ellis, Ian, Greenhalgh, Lynn, Howard, Emma, Stinton, Victoria, Swale, Andrew, Weber, Astrid, Banka, Siddharth, Breen, Catherine, Briggs, Tracy, Burkitt-Wright, Emma, Chandler, Kate, Clayton-Smith, Jill, Donnai, Dian, Douzgou, Sofia, Gaunt, Lorraine, Jones, Elizabeth, Kerr, Bronwyn, Langley, Claire, Metcalfe, Kay, Smith, Audrey, Wright, Ronnie, Bourn, David, Burn, John, Fisher, Richard, Hellens, Steve, Henderson, Alex, Montgomery, Tara, Splitt, Miranda, Straub, Volker, Wright, Michael, Zwolinski, Simon, Allen, Zoe, Bernhard, Birgitta, Brady, Angela, Brooks, Claire, Busby, Louise, Clowes, Virginia, Ghali, Neeti, Holder, Susan, Ibitoye, Rita, Wakeling, Emma, Blair, Edward, Carmichael, Jenny, Cilliers, Deirdre, Clasper, Susan, Gibbons, Richard, Kini, Usha, Lester, Tracy, Nemeth, Andrea, Poulton, Joanna, Price, Sue, Shears, Debbie, Stewart, Helen, Wilkie, Andrew, Albaba, Shadi, Baker, Duncan, Balasubramanian, Meena, Johnson, Diana, Parker, Michael, Quarrell, Oliver, Stewart, Alison, Willoughby, Josh, Crosby, Charlene, Elmslie, Frances, Homfray, Tessa, Jin, Huilin, Lahiri, Nayana, Mansour, Sahar, Marks, Karen, McEntagart, Meriel, Saggar, Anand, Tatton-Brown, Kate, Butler, Rachel, Clarke, Angus, Corrin, Sian, Fry, Andrew, Kamath, Arveen, McCann, Emma, Mugalaasi, Hood, Pottinger, Caroline, Procter, Annie, Sampson, Julian, Sansbury, Francis, Varghese, Vinod, Baralle, Diana, Callaway, Alison, Cassidy, Emma J., Daniels, Stacey, Douglas, Andrew, Foulds, Nicola, Hunt, David, Kharbanda, Mira, Lachlan, Katherine, Mercer, Catherine, Side, Lucy, Temple, I. Karen, Wellesley, Diana, Ambrose, J.C., Arumugam, P., Baple, E.L., Bleda, M., Boardman-Pretty, F., Boissiere, J.M., Boustred, C.R., Caulfield, M.J., Chan, G.C., Craig, C.E.H., Daugherty, L.C., de Burca, A., Devereau, A., Elgar, G., Foulger, R.E., Fowler, T., FurióTarí, P., Hackett, J.M., Halai, D., Hamblin, A., Henderson, S., Holman, J.E., Hubbard, T.J.P., Ibáñez, K., Jackson, R., Jones, L.J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S.E.A., Leong, I.U.S., Lopez, F.J., MaleadyCrowe, F., Mason, J., McDonagh, E.M., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A.C., Odhams, C.A., Patch, C., Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Rendon, A., Riesgo-Ferreiro, P., Rogers, T., Ryten, M., Savage, K., Sawant, K., Scott, R.H., Siddiq, A., Sieghart, A., Smedley, D., Smith, K.R., Sosinsky, A., Spooner, W., Stevens, H.E., Stuckey, A., Sultana, R., Thomas, E.R.A., Thompson, S.R., Tucci, A., Walsh, E., Watters, S.A., Welland, M.J., Williams, E., Witkowska, K., Acosta, Maria T., Adam, Margaret, Adams, David R., Agrawal, Pankaj B., Alejandro, Mercedes E., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Peter Chang, Ta Chen, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D'Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davids, Mariska, Dayal, Jyoti G., Deardorff, Matthew, Dell'Angelica, Esteban C., Dhar, Shweta U., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Douine, Emilie D., Draper, David D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Esteves, Cecilia, Estwick, Tyra, Falk, Marni, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Findley, Laurie C., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Fresard, Laure, Gahl, William A., Glass, Ian, Godfrey, Rena A., Golden-Grant, Katie, Goldman, Alica M., Goldstein, David B., Grajewski, Alana, Groden, Catherine A., Gropman, Andrea L., Gutierrez, Irma, Hahn, Sihoun, Hamid, Rizwan, Hanchard, Neil A., Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yong, Isasi, Rosario, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Johnston, Jean M., Karaviti, Lefkothea, Kelley, Emily G., Kennedy, Jennifer, Kiley, Dana, Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Korrick, Susan, Koziura, Mary, Krier, Joel B., Lalani, Seema R., Lam, Byron, Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., Lau, C. Christopher, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Mak, Bryan, Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Markello, Thomas C., Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McCormack, Colleen E., McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo M., Morimoto, Marie, Mulvihill, John J., Murdock, David R., Nakano-Okuno, Mariko, Nath, Avi, Nelson, Stan F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Papp, Jeanette C., Parker, Neil H., Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Pusey, Barbara N., Quinlan, Aaron, Raskind, Wendy, Raja, Archana N., Rao, Deepak A., Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Scott, C. Ron, Schaechter, Judy, Schedl, Timothy, Scott, Daryl A., Sharma, Prashant, Shin, Jimann, Signer, Rebecca, Sillari, Catherine H., Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Solnica-Krezel, Lilianna, Stoler, Joan M., Stong, Nicholas, Sullivan, Jennifer A., Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tamburro, Cecelia P., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Tucker, Brianna M., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Wallace, Stephanie, Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-Kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Wener, Mark, Wenger, Tara, Perry, Katherine Wesseling, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Woods, Jeremy D., Yamamoto, Shinya, Yang, John, Yu, Guoyun, Zastrow, Diane B., Zhao, Chunli, Zuchner, Stephan, Jeffries, Lauren, Mis, Emily K., McWalter, Kirsty, Donkervoort, Sandra, Brodsky, Nina N., Carpier, Jean-Marie, Ji, Weizhen, Ionita, Cristian, Roy, Bhaskar, Morrow, Jon S., Darbinyan, Armine, Iyer, Krishna, Aul, Ritu B., Chao, Katherine R., Cobbold, Laura, Cohen, Stacey, Custodio, Helena M., Drummond-Borg, Margaret, Finanger, Erika, Hainline, Bryan E., Helbig, Ingo, Hewson, Stacy, Hu, Ying, Jackson, Adam, Konstantino, Monica, Leach, Meganne E., McCormick, David, Nelson, Stanley, Nguyen, Joanne, Nugent, Kimberly, Ortega, Lucy, Goodkin, Howard P., Roeder, Elizabeth, Roy, Sani, Sapp, Katie, Saade, Dimah, Sisodiya, Sanjay M., Stals, Karen, Towner, Shelley, Wilson, William, Khokha, Mustafa K., Bönnemann, Carsten G., Lucas, Carrie L., and Lakhani, Saquib A.

Published
2024
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111. Lunar Volatiles and Solar System Science

Author

Prem, Parvathy, Kereszturi, Ákos, Deutsch, Ariel N., Hibbitts, Charles A., Schmidt, Carl A., Grava, Cesare, Honniball, Casey I., Hardgrove, Craig J., Pieters, Carlé M., Goldstein, David B., Barker, Donald C., Needham, Debra H., Hurley, Dana M., Mazarico, Erwan, Dominguez, Gerardo, Patterson, G. Wesley, Kramer, Georgiana Y., Brisset, Julie, Gillis-Davis, Jeffrey J., Mitchell, Julie L., Szalay, Jamey R., Halekas, Jasper S., Keane, James T., Head, James W., Mandt, Kathleen E., Robinson, Katharine L., Luchsinger, Kristen M., Magaña, Lizeth O., Siegler, Matthew A., Landis, Margaret E., Poston, Michael J., Petro, Noah E., Lucey, Paul G., Killen, Rosemary M., Li, Shuai, Narendranath, Shyama, Shukla, Shashwat, Barrett, Thomas J., Stubbs, Timothy J., Orlando, Thomas M., and Farrell, William M.

Subjects
Astrophysics - Instrumentation and Methods for Astrophysics, Astrophysics - Earth and Planetary Astrophysics
Abstract

Understanding the origin and evolution of the lunar volatile system is not only compelling lunar science, but also fundamental Solar System science. This white paper (submitted to the US National Academies' Decadal Survey in Planetary Science and Astrobiology 2023-2032) summarizes recent advances in our understanding of lunar volatiles, identifies outstanding questions for the next decade, and discusses key steps required to address these questions.

Published
2020

113. The diagnostic yield of exome sequencing in liver diseases from a curated gene panel

Author

Kong, Xiao-Fei, Bogyo, Kelsie, Kapoor, Sheena, Shea, Patrick R., Groopman, Emily E., Thomas-Wilson, Amanda, Cocchi, Enrico, Milo Rasouly, Hila, Zheng, Beishi, Sun, Siming, Zhang, Junying, Martinez, Mercedes, Vittorio, Jennifer M., Dove, Lorna M., Marasa, Maddalena, Wang, Timothy C., Verna, Elizabeth C., Worman, Howard J., Gharavi, Ali G., Goldstein, David B., and Wattacheril, Julia

Published
2023
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114. Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease

Author

Gupta, Yask, Friedman, David J., McNulty, Michelle T., Khan, Atlas, Lane, Brandon, Wang, Chen, Ke, Juntao, Jin, Gina, Wooden, Benjamin, Knob, Andrea L., Lim, Tze Y., Appel, Gerald B., Huggins, Kinsie, Liu, Lili, Mitrotti, Adele, Stangl, Megan C., Bomback, Andrew, Westland, Rik, Bodria, Monica, Marasa, Maddalena, Shang, Ning, Cohen, David J., Crew, Russell J., Morello, William, Canetta, Pietro, Radhakrishnan, Jai, Martino, Jeremiah, Liu, Qingxue, Chung, Wendy K., Espinoza, Angelica, Luo, Yuan, Wei, Wei-Qi, Feng, Qiping, Weng, Chunhua, Fang, Yilu, Kullo, Iftikhar J., Naderian, Mohammadreza, Limdi, Nita, Irvin, Marguerite R., Tiwari, Hemant, Mohan, Sumit, Rao, Maya, Dube, Geoffrey K., Chaudhary, Ninad S., Gutiérrez, Orlando M., Judd, Suzanne E., Cushman, Mary, Lange, Leslie A., Lange, Ethan M., Bivona, Daniel L., Verbitsky, Miguel, Winkler, Cheryl A., Kopp, Jeffrey B., Santoriello, Dominick, Batal, Ibrahim, Pinheiro, Sérgio Veloso Brant, Oliveira, Eduardo Araújo, Simoes e Silva, Ana Cristina, Pisani, Isabella, Fiaccadori, Enrico, Lin, Fangming, Gesualdo, Loreto, Amoroso, Antonio, Ghiggeri, Gian Marco, D’Agati, Vivette D., Magistroni, Riccardo, Kenny, Eimear E., Loos, Ruth J. F., Montini, Giovanni, Hildebrandt, Friedhelm, Paul, Dirk S., Petrovski, Slavé, Goldstein, David B., Kretzler, Matthias, Gbadegesin, Rasheed, Gharavi, Ali G., Kiryluk, Krzysztof, Sampson, Matthew G., Pollak, Martin R., and Sanna-Cherchi, Simone

Published
2023
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116. INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG)

Author

Lam, Lyn Ley, Pavlakis, Nick, Shitara, Kohei, Sjoquist, Katrin M., Martin, Andrew J., Yip, Sonia, Kang, Yoon-Koo, Bang, Yung-Jue, Chen, Li-Tzong, Moehler, Markus, Bekaii-Saab, Tanios, Alcindor, Thierry, O’Callaghan, Christopher J., Tebbutt, Niall C., Hague, Wendy, Chan, Howard, Rha, Sun Young, Lee, Keun-Wook, Gebski, Val, Jaworski, Anthony, Zalcberg, John, Price, Timothy, Simes, John, and Goldstein, David

Published
2023
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117. Shared genetic basis between genetic generalized epilepsy and background electroencephalographic oscillations

Author

Stevelink, Remi, Luykx, Jurjen J, Lin, Bochao D, Leu, Costin, Lal, Dennis, Smith, Alexander W, Schijven, Dick, Carpay, Johannes A, Rademaker, Koen, Baldez, Roiza A Rodrigues, Devinsky, Orrin, Braun, Kees PJ, Jansen, Floor E, Smit, Dirk JA, Koeleman, Bobby PC, Abou‐Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J, Bast, Thomas, Baum, Larry, Becker, Albert J, Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F, Boysen, Katja E, Bradfield, Jonathan P, Brody, Lawrence C, Buono, Russell J, Campbell, Ellen, Cascino, Gregory D, Catarino, Claudia B, Cavalleri, Gianpiero L, Cherny, Stacey S, Chinthapalli, Krishna, Coffey, Alison J, Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J, de Haan, Gerrit‐Jan, De Jonghe, Peter, de Kovel, Carolien GF, Delanty, Norman, Depondt, Chantal, Dlugos, Dennis J, Doherty, Colin P, Elger, Christian E, Eriksson, Johan G, Ferraro, Thomas N, Feucht, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A, Freytag, Saskia, Gaus, Verena, Geller, Eric B, Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B, Gui, Hongsheng, Guo, Youling, Haas, Kevin F, Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L, Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andrés, Jamnadas‐Khoda, Jennifer, Johnson, Michael R, Kälviäinen, Reetta, Kantanen, Anne‐Mari, Kasperavičiūte, Dalia, Trenite, Dorothee Kasteleijn‐Nolst, Kirsch, Heidi E, Knowlton, Robert C, Krause, Roland, Krenn, Martin, Kunz, Wolfram S, Kuzniecky, Ruben, Kwan, Patrick, Lau, Yu‐Lung, Lehesjoki, Anna‐Elina, Lerche, Holger, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D, Lopes‐Cendes, Iscia, Lowenstein, Daniel H, Malovini, Alberto, Marson, Anthony G, Mayer, Thomas, McCormack, Mark, and Mills, James L

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Genetics, Brain Disorders, Clinical Research, Human Genome, Neurodegenerative, Epilepsy, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Algorithms, Beta Rhythm, Cohort Studies, Databases, Factual, Electroencephalography, Epilepsy, Generalized, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Mendelian Randomization Analysis, Risk Assessment, Theta Rhythm, beta power, EEG, generalized epilepsy, GGE, oscillations, PRS, International League Against Epilepsy Consortium on Complex Epilepsies, Epi25 Collaborative, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.

Published
2021

118. Antibodies to SARS-CoV-2 in All of Us Research Program Participants, January 2-March 18, 2020.

Author

Althoff, Keri N, Schlueter, David J, Anton-Culver, Hoda, Cherry, James, Denny, Joshua C, Thomsen, Isaac, Karlson, Elizabeth W, Havers, Fiona P, Cicek, Mine S, Thibodeau, Stephen N, Pinto, Ligia A, Lowy, Douglas, Malin, Bradley A, Ohno-Machado, Lucila, Williams, Carolyn, Goldstein, David, Kouame, Aymone, Ramirez, Andrea, Roman, Adrienne, Sharpless, Norman E, Gebo, Kelly A, and Schully, Sheri D

Subjects
All of Us Research Program, SARS-CoV-2 antibodies, United States, Emerging Infectious Diseases, Biodefense, Prevention, Vaccine Related, Clinical Research, Microbiology, Biological Sciences, Medical and Health Sciences
Abstract

BackgroundWith limited SARS-CoV-2 testing capacity in the US at the start of the epidemic (January - March), testing was focused on symptomatic patients with a travel history throughout February, obscuring the picture of SARS-CoV-2 seeding and community transmission. We sought to identify individuals with SARS-CoV-2 antibodies in the early weeks of the US epidemic.MethodsAll of Us study participants in all 50 US states provided blood specimens during study visits from January 2 to March 18, 2020. A participant was considered seropositive if they tested positive for SARS-CoV-2 immunoglobulin G (IgG) antibodies on the Abbott Architect SARS-CoV-2 IgG ELISA and the EUROIMMUN SARS-CoV-2 ELISA in a sequential testing algorithm. Sensitivity and specificity of the Abbott and EUROIMMUNE ELISAs and the net sensitivity and specificity of the sequential testing algorithm were estimated with 95% confidence intervals.ResultsThe estimated sensitivity of Abbott and EUROIMMUN was 100% (107/107 [96.6%, 100%]) and 90.7% (97/107 [83.5%, 95.4%]), respectively. The estimated specificity of Abbott and EUROIMMUN was 99.5% (995/1,000 [98.8%, 99.8%]) and 99.7% (997/1,000 [99.1%, 99.9%), respectively. The net sensitivity and specificity of our sequential testing algorithm was 90.7% (97/107 [83.5%, 95.4%]) and 100.0% (1,000/1,000 [99.6%, 100%]), respectively. Of the 24,079 study participants with blood specimens from January 2 to March 18, 2020, 9 were seropositive, 7 of whom were seropositive prior to the first confirmed case in the states of Illinois, Massachusetts, Wisconsin, Pennsylvania, and Mississippi.ConclusionsOur findings indicate SARS-CoV-2 infections weeks prior to the first recognized cases in 5 US states.

Published
2021

119. Preclinical Efficacy and Anti-Inflammatory Mechanisms of Action of the Bruton Tyrosine Kinase Inhibitor Rilzabrutinib for Immune-Mediated Disease.

Author

Langrish, Claire L, Bradshaw, J Michael, Francesco, Michelle R, Owens, Timothy D, Xing, Yan, Shu, Jin, LaStant, Jacob, Bisconte, Angelina, Outerbridge, Catherine, White, Stephen D, Hill, Ronald J, Brameld, Ken A, Goldstein, David M, and Nunn, Philip A

Subjects
Kidney, Blood Platelets, Basophils, Mast Cells, Animals, Dogs, Humans, Mice, Nephritis, Purpura, Thrombocytopenic, Idiopathic, Pemphigus, Disease Models, Animal, Immunoglobulin E, Anti-Inflammatory Agents, Protein Kinase Inhibitors, Drug Evaluation, Preclinical, Mice, 129 Strain, Agammaglobulinaemia Tyrosine Kinase, Autoimmune Disease, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Inflammatory and immune system, Immunology
Abstract

Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK inhibition has the potential to target multiple immune-mediated disease pathways. Rilzabrutinib is an oral, reversible, covalent BTK inhibitor designed for immune-mediated diseases. We examined the pharmacodynamic profile of rilzabrutinib and its preclinical mechanisms of action. In addition to potent and selective BTK enzyme and cellular activity, rilzabrutinib inhibited activation and inflammatory activities of B cells and innate cells such as macrophages, basophils, mast cells, and neutrophils, without cell death (in human and rodent assay systems). Rilzabrutinib demonstrated dose-dependent improvement of clinical scores and joint pathology in a rat model of collagen-induced arthritis and demonstrated reductions in autoantibody-mediated FcγR signaling in vitro and in vivo, with blockade of rat Arthus reaction, kidney protection in mouse Ab-induced nephritis, and reduction in platelet loss in mouse immune thrombocytopenia. Additionally, rilzabrutinib inhibited IgE-mediated, FcεR-dependent immune mechanisms in human basophils and mast cell-dependent mouse models. In canines with naturally occurring pemphigus, rilzabrutinib treatment resulted in rapid clinical improvement demonstrated by anti-inflammatory effects visible within 2 wk and all animals proceeding to complete or substantial disease control. Rilzabrutinib is characterized by reversible covalent BTK binding, long BTK residence time with low systemic exposure, and multiple mechanistic and biological effects on immune cells. Rilzabrutinib's unique characteristics and promising efficacy and safety profile support clinical development of rilzabrutinib for a broad array of immune-mediated diseases.

Published
2021

120. Cardiac noradrenergic deficiency revealed by [sup.18]F-dopamine positron emission tomography identifies preclinical central Lewy body diseases

Author

Goldstein, David S., Holmes, Courtney, Sullivan, Patti, Lopez, Grisel, Gelsomino, Janna, Moore, Sarah, Isonaka, Risa, Wu, Tianxia, and Sharabi, Yehonatan

Subjects
Aging -- Health aspects, PET imaging -- Analysis, Lewy body disease -- Diagnosis -- Care and treatment -- Genetic aspects, Sympathectomy -- Patient outcomes, Health care industry
Abstract

BACKGROUND. In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac [sup.18]F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals. METHODS. Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 or more confirmed risk factors underwent serial cardiac [sup.18]F-dopamine PET at 1.5-year intervals for up to 7.5 years or until PD was diagnosed. RESULTS. Nine participants had low initial myocardial [sup.18]F-dopamine-derived radioactivity ( CONCLUSION. Cardiac [sup.18]F-dopamine PET highly efficiently distinguishes at- risk individuals who are diagnosed subsequently with a central LBD from those who are not. TRIAL REGISTRATION. ClinicalTrials.gov NCT00775853. FUNDING. Division of Intramural Research, NIH, NINDS., Introduction Aging-related neurodegenerative diseases are posing an increasing public health burden as populations are getting older. Prominent among these conditions are the central Lewy body diseases (LBDs), Parkinson disease (PD), [...]

Published
2024
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121. Patient-reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after treatment with imatinib in INTRIGUE, a phase 3, open-label study

Author

Gelderblom, Hans, Jones, Robin L., Blay, Jean-Yves, George, Suzanne, von Mehren, Margaret, Zalcberg, John R., Kang, Yoon-Koo, Razak, Albiruni Abdul, Trent, Jonathan, Attia, Steven, Le Cesne, Axel, Siontis, Brittany L., Goldstein, David, Boye, Kjetil, Sanchez, Cesar, Steeghs, Neeltje, Rutkowski, Piotr, Druta, Mihaela, Serrano, César, Somaiah, Neeta, Chi, Ping, Harrow, Brooke, Becker, Claus, Reichmann, William, Sherman, Matthew L., Ruiz-Soto, Rodrigo, Heinrich, Michael C., and Bauer, Sebastian

Published
2023
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122. Implication of dental insurance status on patterns of pre-radiation dental extraction and risk of osteoradionecrosis of the jaw in head-and-neck cancer patients

Author

Watson, Erin, El Maghrabi, Amr, Lee, Jun Hyung, Pu, Jiajie, Xu, Wei, Joudah, Shahad, D'Souza, Violet, Quiñonez, Carlos, Mojdami, Zahra Dorna, Huang, Shao Hui, O'Sullivan, Brian, Ringash, Jolie, Kim, John, Cho, John, Bratman, Scott, Waldron, John, Goldstein, David, Abdalaty, Ali Hosni, Glogauer, Michael, and Hope, Andrew

Published
2023
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123. The impact of surgical resection margins on outcomes for adults with head and neck osteosarcomas: A Canadian sarcoma research and Clinical Collaboration (CanSaRCC) study

Author

Tzelnick, Sharon, Soroka, Hagit Peretz, Tasnim, Najifah, Gilbert, Ralph W., Irish, Jonathan C., Goldstein, David P., Brown, Dale, Gullane, Patrick, Chepeha, Douglas B., Yao, Christopher M.K.L., Sahovaler, Axel, Witterick, Ian J., Monteiro, Eric, Davies, Joel, Huang, Shao Hui, O'Sullivan, Brian, Hahn, Ezra, Hosni, Ali, Razak, Albiruni Abdul, Gupta, Abha A., and de Almeida, John R.

Published
2023
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124. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

Author

Chia, Ruth, Sabir, Marya S, Bandres-Ciga, Sara, Saez-Atienzar, Sara, Reynolds, Regina H, Gustavsson, Emil, Walton, Ronald L, Ahmed, Sarah, Viollet, Coralie, Ding, Jinhui, Makarious, Mary B, Diez-Fairen, Monica, Portley, Makayla K, Shah, Zalak, Abramzon, Yevgeniya, Hernandez, Dena G, Blauwendraat, Cornelis, Stone, David J, Eicher, John, Parkkinen, Laura, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence S, Marder, Karen, Lemstra, Afina, St George-Hyslop, Peter, Londos, Elisabet, Morgan, Kevin, Lashley, Tammaryn, Warner, Thomas T, Jaunmuktane, Zane, Galasko, Douglas, Santana, Isabel, Tienari, Pentti J, Myllykangas, Liisa, Oinas, Minna, Cairns, Nigel J, Morris, John C, Halliday, Glenda M, Van Deerlin, Vivianna M, Trojanowski, John Q, Grassano, Maurizio, Calvo, Andrea, Mora, Gabriele, Canosa, Antonio, Floris, Gianluca, Bohannan, Ryan C, Brett, Francesca, Gan-Or, Ziv, Geiger, Joshua T, Moore, Anni, May, Patrick, Krüger, Rejko, Goldstein, David S, Lopez, Grisel, Tayebi, Nahid, Sidransky, Ellen, Norcliffe-Kaufmann, Lucy, Palma, Jose-Alberto, Kaufmann, Horacio, Shakkottai, Vikram G, Perkins, Matthew, Newell, Kathy L, Gasser, Thomas, Schulte, Claudia, Landi, Francesco, Salvi, Erika, Cusi, Daniele, Masliah, Eliezer, Kim, Ronald C, Caraway, Chad A, Monuki, Edwin S, Brunetti, Maura, Dawson, Ted M, Rosenthal, Liana S, Albert, Marilyn S, Pletnikova, Olga, Troncoso, Juan C, Flanagan, Margaret E, Mao, Qinwen, Bigio, Eileen H, Rodríguez-Rodríguez, Eloy, Infante, Jon, Lage, Carmen, González-Aramburu, Isabel, Sanchez-Juan, Pascual, Ghetti, Bernardino, Keith, Julia, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Duyckaerts, Charles, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Barrett, Matthew J, Tilley, Bension S, Gentleman, Steve, Logroscino, Giancarlo, and Serrano, Geidy E

Subjects
Biological Sciences, Genetics, Human Genome, Alzheimer's Disease Related Dementias (ADRD), Prevention, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Aging, Dementia, Brain Disorders, Acquired Cognitive Impairment, Lewy Body Dementia, Biotechnology, Parkinson's Disease, Neurosciences, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Case-Control Studies, Gene Expression Profiling, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Glucosylceramidase, Humans, Lewy Body Disease, Nuclear Proteins, Parkinson Disease, Polymorphism, Single Nucleotide, Tumor Suppressor Proteins, alpha-Synuclein, American Genome Center, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Published
2021

125. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

Author

Weng, Patricia, Majmundar, Amar, Khan, Kamal, Lim, Tze, Shril, Shirlee, Jin, Gina, Musgrove, John, Wang, Minxian, Ahram, Dina, Aggarwal, Vimla, Bier, Louise, Heinzen, Erin, Onuchic-Whitford, Ana, Mann, Nina, Buerger, Florian, Schneider, Ronen, Deutsch, Konstantin, Kitzler, Thomas, Klämbt, Verena, Kolb, Amy, Mao, Youying, Moufawad El Achkar, Christelle, Mitrotti, Adele, Martino, Jeremiah, Beck, Bodo, Altmüller, Janine, Benz, Marcus, Yano, Shoji, Mikati, Mohamad, Gunduz, Talha, Cope, Heidi, Shashi, Vandana, Trachtman, Howard, Bodria, Monica, Caridi, Gianluca, Pisani, Isabella, Fiaccadori, Enrico, AbuMaziad, Asmaa, Martinez-Agosto, Julian, Yadin, Ora, Zuckerman, Jonathan, Kim, Arang, John-Kroegel, Ulrike, Tyndall, Amanda, Parboosingh, Jillian, Innes, A, Bierzynska, Agnieszka, Koziell, Ania, Muorah, Mordi, Saleem, Moin, Hoefele, Julia, Riedhammer, Korbinian, Gharavi, Ali, Jobanputra, Vaidehi, Pierce-Hoffman, Emma, Seaby, Eleanor, ODonnell-Luria, Anne, Rehm, Heidi, Mane, Shrikant, DAgati, Vivette, Pollak, Martin, Ghiggeri, Gian, Lifton, Richard, Goldstein, David, Davis, Erica, Hildebrandt, Friedhelm, and Sanna-Cherchi, Simone

Subjects
FSGS, SRNS, TRIM8, epilepsy, genomics, monogenic, nuclear body, Adult, Animals, Carrier Proteins, Cell Line, Child, Child, Preschool, Codon, Nonsense, Developmental Disabilities, Epilepsy, Female, Glomerulosclerosis, Focal Segmental, Humans, Intranuclear Space, Kidney, Male, Mice, Mutation, Nephrotic Syndrome, Nerve Tissue Proteins, Phenotype, Podocytes, Exome Sequencing
Abstract

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Published
2021

126. Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science.

Author

Schoch, Kelly, Esteves, Cecilia, Bican, Anna, Spillmann, Rebecca, Cope, Heidi, McConkie-Rosell, Allyn, Walley, Nicole, Fernandez, Liliana, Kohler, Jennefer N, Bonner, Devon, Reuter, Chloe, Stong, Nicholas, Mulvihill, John J, Novacic, Donna, Wolfe, Lynne, Abdelbaki, Ayat, Toro, Camilo, Tifft, Cyndi, Malicdan, May, Gahl, William, Liu, Pengfei, Newman, John, Goldstein, David B, Hom, Jason, Sampson, Jacinda, Wheeler, Matthew T, Undiagnosed Diseases Network, Cogan, Joy, Bernstein, Jonathan A, Adams, David R, McCray, Alexa T, and Shashi, Vandana

Subjects
Undiagnosed Diseases Network, Animals, Humans, Rare Diseases, Retrospective Studies, Genomics, Undiagnosed Diseases, Exome Sequencing, exome sequencing, genome sequencing, phenotyping, ultrarare diseases, undiagnosed diseases, Human Genome, Genetics, Biotechnology, Good Health and Well Being, Clinical Sciences, Genetics & Heredity
Abstract

PurposeThe NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices.MethodsWe analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods.ResultsOf 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling.ConclusionInvestigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.

Published
2021

131. D-DEMØ, a distinct phenotype caused by ATP1A3 mutations.

Author

Schiffmann, Raphael, Mueller, David, McLean, Melissa, Mendez, Mary, Walley, Nicole, Heinzen, Erin, Goldstein, David, Shashi, Vandana, Hunanyan, Arsen, Pagadala, Vijay, Mikati, Mohamad, Prange, Lyndsey, Pratt, Milton, and Herman, Kristin

Abstract

OBJECTIVE: To describe a phenotype caused by ATP1A3 mutations, which manifests as dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø) (D-DEMØ), and neonatal onset. METHODS: Review and analysis of clinical and genetic data. RESULTS: Patients shared the above traits and had whole-exome sequencing that showed de novo variants of the ATP1A3 gene, predicted to be disease causing and occurring in regions of the protein critical for pump function. Patient 1 (c.1079C>G, p.Thr360Arg), an 8-year-old girl, presented on day 1 of life with episodic dystonia, complex partial seizures, and facial dysmorphism. MRI of the brain revealed cerebellar hypoplasia. Patient 2 (c.420G>T, p.Gln140His), an 18-year-old man, presented on day 1 of life with hypotonia, tremor, and facial dysmorphism. He later developed dystonia. MRI of the brain revealed cerebellar hypoplasia and, later, further cerebellar volume loss (atrophy). Patient 3 (c.974G>A, Gly325Asp), a 13-year-old girl, presented on day 1 of life with tremor, episodic dystonia, and facial dysmorphism. MRI of the brain showed severe cerebellar hypoplasia. Patient 4 (c.971A>G, p.Glu324Gly), a 14-year-old boy, presented on day 1 of life with tremor, hypotonia, dystonia, nystagmus, facial dysmorphism, and later seizures. MRI of the brain revealed moderate cerebellar hypoplasia. CONCLUSIONS: D-DEMØ represents an ATP1A3-related phenotype, the observation of which should trigger investigation for ATP1A3 mutations. Our findings, and the presence of multiple distinct ATP1A3-related phenotypes, support the possibility that there are differences in the underlying mechanisms.

Published
2020

132. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author

Soltis, Anthony R., Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, McGrath Martinez, Elisa, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N., Adeleye, Adelani, Wilkerson, Matthew D., Pollard, Harvey B., Dalgard, Clifton L., Black, Sandra E., Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A., Hodges, Angela K., Love, Seth, McKeith, Ian G., Morris, Christopher M., Morris, Huw R., Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J., Troakes, Claire, Albert, Marilyn S., Barrett, Matthew J., Beach, Thomas G., Bekris, Lynn M., Bennett, David A., Boeve, Bradley F., Dawson, Ted M., Dickson, Dennis W., Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E., Foroud, Tatiana M., Ghetti, Bernardino, Gibbs, J. Raphael, Goate, Alison, Goldstein, David S., Graff-Radford, Neill R., Kaufmann, Horacio, Kukull, Walter A., Leverenz, James B., Lopez, Grisel, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L., Palma, Jose-Alberto, Perkins, Matthew, Pletnikova, Olga, Renton, Alan E., Resnick, Susan M., Rosenthal, Liana S., Ross, Owen A., Scherzer, Clemens R., Serrano, Geidy E., Shakkottai, Vikram G., Sidransky, Ellen, Tanaka, Toshiko, Tayebi, Nahid, Topol, Eric, Torkamani, Ali, Troncoso, Juan C., Woltjer, Randy, Wszolek, Zbigniew K., Scholz, Sonja W., Baloh, Robert H., Bowser, Robert, Broach, James, Camu, William, Chiò, Adriano, Cooper-Knock, John, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Feldman, Eva, Fratta, Pietro, Gerhard, Glenn, Gibson, Summer B., Glass, Jonathan D., Harms, Matthew B., Heiman-Patterson, Terry D., Jansson, Lilja, Kirby, Janine, Kwan, Justin, Laaksovirta, Hannu, Landers, John E., Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J.L., Maragakis, Nicholas J., Mouzat, Kevin, Myllykangas, Liisa, Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pioro, Erik, Pulst, Stefan M., Ravits, John M., Robberecht, Wim, Rothstein, Jeffrey D., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Stein, Thor, Stone, David J., Tienari, Pentti J., Traynor, Bryan J., Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, Zinman, Lorne, Kaivola, Karri, Chia, Ruth, Ding, Jinhui, Rasheed, Memoona, Fujita, Masashi, Menon, Vilas, Walton, Ronald L., Collins, Ryan L., Billingsley, Kimberley, Brand, Harrison, Talkowski, Michael, Zhao, Xuefang, Dewan, Ramita, Stark, Ali, Ray, Anindita, Solaiman, Sultana, Alvarez Jerez, Pilar, Malik, Laksh, Tienari, Pentti, Mazzini, Letizia, D'Alfonso, Sandra, Moglia, Cristina, and De Jager, Philip L.

Published
2023
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133. Self-organized yolk sac-like organoids allow for scalable generation of multipotent hematopoietic progenitor cells from induced pluripotent stem cells

Author

Tamaoki, Naritaka, Siebert, Stefan, Maeda, Takuya, Ha, Ngoc-Han, Good, Meghan L., Huang, Yin, Vodnala, Suman K., Haro-Mora, Juan J., Uchida, Naoya, Tisdale, John F., Sweeney, Colin L., Choi, Uimook, Brault, Julie, Koontz, Sherry, Malech, Harry L., Yamazaki, Yasuhiro, Isonaka, Risa, Goldstein, David S., Kimura, Masaki, Takebe, Takanori, Zou, Jizhong, Stroncek, David F., Robey, Pamela G., Kruhlak, Michael J., Restifo, Nicholas P., and Vizcardo, Raul

Published
2023
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134. Napabucasin plus nab-paclitaxel with gemcitabine versus nab-paclitaxel with gemcitabine in previously untreated metastatic pancreatic adenocarcinoma: an adaptive multicentre, randomised, open-label, phase 3, superiority trial

Author

Bekaii-Saab, Tanios, Okusaka, Takuji, Goldstein, David, Oh, Do-Youn, Ueno, Makoto, Ioka, Tatsuya, Fang, Weijia, Anderson, Eric C., Noel, Marcus S., Reni, Michele, Choi, Hye Jin, Goldberg, Jonathan S., Oh, Sang Cheul, Li, Chung-Pin, Tabernero, Josep, Li, Jian, Foos, Emma, Oh, Cindy, and Van Cutsem, Eric

Published
2023
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141. Contributors

Author

Accorsi–Mendonça, Daniela, primary, Adams, David J., additional, Allen, Andrew M., additional, Alvarenga, Marlies, additional, Ardell, Jeffrey L., additional, Arnold, Amy C., additional, Ashton, Jesse L., additional, Badrov, Mark B., additional, Ballantyne, Brennan A., additional, Bardsley, Emma N., additional, Barez-Lopez, Soledad, additional, Barman, Susan M., additional, Barrett, Carolyn J., additional, Bauer, Deborah, additional, Bell, Christopher, additional, Ben-Tal, Alona, additional, Benarroch, Eduardo E., additional, Biaggioni, Italo, additional, Brandl, Katharina, additional, Brooks, Virginia L., additional, Brown, Amy E., additional, Browning, Kirsteen N., additional, Bryarly, Meredith, additional, Camargo, Livia L., additional, Camilleri, Michael, additional, Campbell, Preston J., additional, Caron, Marc G., additional, Carter, Jason R., additional, Chapleau, Mark W., additional, Charkoudian, Nisha, additional, Chelimsky, Gisela, additional, Chelimsky, Thomas C., additional, Chompoopong, Pitcha, additional, Claydon, Victoria E., additional, Clément, Gilles, additional, Convertino, Victor A., additional, Coon, Elizabeth A., additional, Cortelli, Pietro, additional, Davis, Stephen N., additional, Diedrich, André, additional, DiPette, Donald J., additional, Diz, Debra I., additional, Drake, Marcus J., additional, Eisenhofer, Graeme, additional, Elefteriou, Florent, additional, Elijovich, Fernando, additional, Elmenhorst, Eva-Maria, additional, English, Brett A., additional, Esler, Murray, additional, Esler, Rosemary, additional, Fadel, Paul J., additional, Fahrenholz, John M., additional, Fanciulli, Alessandra, additional, Fang, John Y., additional, Fealey, Robert D., additional, Ferreira, Nathanne S., additional, Filogonio, Renato, additional, Fink, Gregory D., additional, Fisher, James P., additional, Floras, John S., additional, Fountain, Samuel J., additional, Fu, Qi, additional, Fudim, Marat, additional, Furlan, Raffaello, additional, Gamboa, Alfredo, additional, Garland, Emily M., additional, Gibbons, Christopher H., additional, Giritharan, Andrew, additional, Goldstein, David S., additional, Golombék, Diego A., additional, Gomez-Sanchez, Elise P., additional, Gomez-Sanchez, Celso E., additional, Graham, Robert M., additional, Grassi, Guido, additional, Greenlund, Ian M., additional, Grubb, Blair P., additional, Guekht, Alla, additional, Guild, Sarah-Jane, additional, Guo, Ling, additional, Gurevich, Vsevolod V., additional, Habermann, Ralf, additional, Hadaya, Joseph, additional, Hahn, Maureen K., additional, Hanna, Peter, additional, Henderson, Luke A., additional, Herring, Neil, additional, Hilz, Max J., additional, Hunter, Peter, additional, Hyland, Keith, additional, Hyland, Lauren A., additional, Jackson, Edwin Kerry, additional, Jacob, Giris, additional, Jänig, Wilfrid, additional, Japundžić-Žigon, Nina, additional, Jones, Carrie K., additional, Joos, Karen M., additional, Jordan, Jens, additional, Joyce, William, additional, Kaidonis, Xenia, additional, Kaufmann, Horacio, additional, Kaye, David, additional, Khan Minhas, Abdul Mannan, additional, Kim, Joyce S., additional, Kitta, Takeya, additional, Kline, David D., additional, Konecny, Thomas, additional, Koons, Natalie J., additional, Kumar, Ambrish, additional, Laffer, Cheryl L., additional, Lagrange, Andre H., additional, Laiken, Nora, additional, Lambert, Gavin, additional, Lambert, Elisabeth, additional, Lamotte, Guillaume, additional, Lenders, Jacques W.M., additional, Levine, Benjamin D., additional, Leys, Fabian, additional, Limper, Ulrich, additional, Lin, Mabelle, additional, Listik, Eduardo, additional, Longmuir, Reid, additional, Low, David A., additional, Low, Phillip A., additional, Luther, James M., additional, Macefield, Vaughan G., additional, Machado, Benedito H., additional, Madel, Maria-Bernadette, additional, Martelli, Davide, additional, Mathias, Christopher J., additional, Mauermann, Michelle L., additional, McAllen, Robin M., additional, McBryde, Fiona D., additional, McKeon, Andrew, additional, McKinley, Michael J., additional, Menuet, Clément, additional, Milam, Douglas F., additional, Mohl, Marion C., additional, Montgomery, Johanna M., additional, Moraes, Davi J.A., additional, Morrison, Shaun F., additional, Murphy, David, additional, Nichols, Charles D., additional, Niewiński, Piotr, additional, Norcliffe-Kaufmann, Lucy, additional, Okamoto, Luis E., additional, Osanlouy, Mahyar, additional, Osborn, John W., additional, Oubaid, Viktor, additional, Palma, Jose-Alberto, additional, Pamporaki, Christina, additional, Parsons, Brian A., additional, Paterson, David J., additional, Paton, Julian F.R., additional, Peltier, Amanda C., additional, Pensato, Umberto, additional, Peterson, Sean M., additional, Phibbs, Fenna T., additional, Pierangeli, Giulia, additional, Potts, Jay D., additional, Rabinstein, Alejandro A., additional, Raizada, Mohan K., additional, Raj, Satish R., additional, Rand, Casey M., additional, Reichmann, Heinz, additional, Robertson, Calum, additional, Robertson, Rose Marie, additional, Robinson, Michael B., additional, Ruzieh, Mohammed, additional, Sandroni, Paola, additional, Sato, Takayuki, additional, Schiffrin, Ernesto L., additional, Schlaich, Markus, additional, Schondorf, Ronald, additional, Schultz, Harold D., additional, Scott, Michael M., additional, Seravalle, Gino, additional, Shannon, John R., additional, Sheikh, Abu Baker, additional, Shibao, Cyndya A., additional, Shivkumar, Kalyanam, additional, Shouman, Kamal, additional, Siepmann, Timo, additional, Singer, Wolfgang, additional, Soltani, Elias, additional, Somers, Virend, additional, Sridharan, Aadhavi, additional, Stefanova, Nadia, additional, Stewart, Julian, additional, Stiles, Lauren E., additional, Sunagawa, Kenji, additional, Tank, Jens, additional, Thijs, Roland D., additional, Tomek, Jakub, additional, Touyz, Rhian M., additional, Tracy, Jennifer A., additional, Travagli, R. Alberto, additional, Undem, Bradley J., additional, Urs, Nikhil, additional, Vernino, Steven, additional, Vianna, Lauro C., additional, Vigo, Daniel E., additional, Vizzard, Margaret A., additional, Wahba, Amr, additional, Waheed, Waqar, additional, Wang, Han-Jun, additional, Wang, Tobias, additional, Wang, Qin, additional, Wang, Ruihao, additional, Weese-Mayer, Debra E., additional, Wenning, Gregor K., additional, Wieling, Wouter, additional, Williams, Kevin W., additional, Winzer-Serhan, Ursula H., additional, Wood, Scott, additional, Yap, Kai Lee, additional, Yoshimura, Naoki, additional, Zavalin, Kirill A., additional, Zhuravlev, Dmitry, additional, Zoccal, Daniel B., additional, and Zubcevic, Jasenka, additional

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2023
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