3,278 results on '"G Martin"'
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2. [On psychiatric rehabilitation in the USSR].
- Author
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MARTIN G
- Subjects
- Humans, USSR, Medicine, Mental Disorders rehabilitation, Psychotherapy
- Published
- 1959
3. Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study
- Author
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T Richards, S Shaikh, S Rehman, A Khan, J Shah, C Smith, A Brown, S Singh, A P Arnaud, A Young, D Bowen, P Patel, S Williams, J Dunn, J John, M Loubani, A Hainsworth, A Kolias, PJ Hutchinson, R Singh, S Sinha, S Shaw, J Edwards, S Mukherjee, AAB Jamjoom, A Singh, S Saeed, J Martin, S Smith, S Ross, M Mohan, P Hutchinson, G James, RDC Moon, P Brennan, A Williams, S Brown, A Ward, M Lee, K Thompson, S Ali, J Williams, S Reid, U Khan, J Lambert, A Smith, B Singh, M Hassan, N Sharma, J Reynolds, N Wright, T Williams, H Smith, M Ng, M Rahman, A Taylor, P Shah, D Saxena, J Evans, I Omar, M Ali, A Hanson, Z Li, R Andrade, P Cardoso, H Jeong, P Sharma, M Arrieta, J Clark, L Pearce, J McVeigh, V Sharma, B Kim, J Singh, S Newman, J Byrne, A Hassan, A Persad, A Gardner, H Liu, K Shah, I Hughes, S Davison, A Balakrishnan, K Patel, J Hall, S Mistry, J Parry, R Baumber, N McGrath, E Ross, R Mannion, S Murphy, FL Wright, A Rogers, B Rai, M Thomas, R Ribeiro, E Hamilton, J Teixeira, B Davidson, L Carvalho, R Garrido, A Puppo, A Guimarães, E Santos, M Kamal, M Denning, M Elhadi, J E Fitzgerald, D Miller, M Gowda, C Morris, A Phillips, H Yang, Y Zhang, N Machairas, A Fisher, A Kaufmann, A Aggarwal, L Hansen, M Otify, H Soleymani Majd, A Jones, M Rodrigues, S Sundar, C Jones, R Edmondson, A Sharkey, L Smith, G Williams, J Dunning, E Belcher, D Stavroulias, V Zamvar, M Patel, M Baker, R Evans, M Sherif, J Hopkins, R Mohammed, A Hill, H Jackson, G Jones, K George, J Dixon, A Tong, S Jallad, Deborah S Keller, A Pereira, L Elliott, D Ford, A Sermon, M Almond, Andrew Metcalfe, C Peluso, T White, S Shah, A Witek, Chetan Khatri, A Tiwari, T Lo, K Agarwal, C Sweeney, C Hart, T Holme, S Green, I Ahmed, A Sobti, C Anderson, N Modi, R Campbell, C Magee, M Mirza, D Jones, N Stylianides, X Luo, C Kang, J Ribeiro, L Kumar, J Diaz, A Bhalla, R Young, C Perkins, A James, A Walters, J Reid, R Pereira, C McDonald, A Aujayeb, K Jackson, M Allen, D Ghosh, M Chan, C Price, K Khan, R Moore, M Ibrahim, A Marchbank, M Silva, M Baig, J De Coster, J Castellanos, S Saxena, M Duque, E Li, E Martin, A Isik, J González, RJ Davies, B Smith, R Owen, K Lakhoo, M Rogers, MA Akhtar, K Mellor, S Agrawal, L Foster, G Harris, J McIntyre, M Garner, R West, R Cuthbert, D Johnson, H Gomes, C Roy, N Spencer, D Mehta, J Freedman, J Blair, K Rajput, K Williams, J Wall, A Soliman, F Chen, A Mokhtari, I Mohamed, J Pascoe, M Khalifa, R Das, A Lara, M Costa, A Mahmoud, K Roberts, J Lane, S Robertson, J P Evans, E Krishnan, I Haq, S Rogers, J Knowles, M Chowdhury, A Ghanbari, L Macdonald, S Powell, J Hunt, J Cornish, J Engel, S Page, I Blake, A Rolls, H Ross, D Simpson, J Hammond, A Goyal, K Parkins, A Desai, A Gaunt, A Salim, Y Yousef, A Schache, H Mohan, SR Brown, R Nair, M Flatman, J Lord, RJ Egan, R Harries, N Judkins, K Sugand, T Hine, J Luck, C Johnson, G Salerno, AW Phillips, R Houston, A Volpe, C Walker, C Steele, M Rela, C Barry, R Alves, L Ramsay, A Turnbull, A Daniele, C S Jones, P Gallagher, G Gradinariu, A Oliveira, C Hardie, H Ferguson, S Bhattacharya, E Davies, P Joshi, C Mellor, E Griffiths, A Bhangu, R Mahoney, F Kashora, G Ruiz, K Wong, G Hill, V Testa, S Ford, C Park, P Gomez, C Lopes, A Lázaro, A Shabana, A Agarwal, C Chung, C Politis, G Martin, E Chung, M Ismail, C Cunha, S Correia, I Santos, A Tang, A Robson, T Collier, G Baltazar, M Quintana, C English, M Ip, K Newton, J Kahn, C Tan, D Cheng, R Woods, M Ho, A ABBAS, A Henry, F Rivas, M Mohammed, N Parsons, T Board, S Madan, A Osorio, M Jarvis, M Hashem, A Egglestone, E Halliday, A Ridgway, G Gallo, J Gilliland, W Marx, R Shaw, A Mahmood, K Gohil, B Gallagher, D Alderson, A Karim, G D Stewart, G Peck, L Majkowski, J Carter, H Ishii, L HUMPHREYS, J Khan, S Abbott, C Newton, F Borghi, A Sud, K Bhatia, H Cao, V Vijay, L Sanderson, E Holler, N Hanna, D Ferguson, P Miranda, L Pickering, T Singhal, T Newman, K Ghosh, C Camacho, D Manning, C Lipede, R Clifford, S Higgs, C Menakaya, S Shankar, K Booth, M Abdalla, T Nelson, T Farrell, H Naseem, J Johnstone, A Wilkins, A Brunt, A Nogués, A Patience, D Jeevan, M Vatish, G Stables, S Adegbola, I Hunt, K Dickson, W Matthews, N Dunne, M Maher, G Faulkner, E Hernandez, R Sofat, K Sahnan, A Brunelli, M Raza, K Chui, C Brennan, P Vaughan, H Chu, R Hagger, ASD Liyanage, R Perkins, S Duff, C Gill, H Dean, S Bandyopadhyay, K Ragupathy, Y Cunningham, A Bateman, V Brown, B Ho, E Britton, H Ikram, R Hasan, A Colquhoun, S Handa, A Maqsood, M Caputo, J Torkington, G Fusai, N Hossain, DJ Lin, S Stefan, IR Daniels, D Pournaras, A Askari, P Nisar, S Moug, J Sagar, N Yassin, G Minto, Z Hamady, JR O'Neill, S Chowdhury, R Cresner, D Vimalachandran, FD Mcdermott, RP Jones, P Zerbib, L Sreedharan, S Wahed, SS Gisbertz, MI van Berge Henegouwen, R Preece, I Liew, S McCluney, D Watts, D Nehra, B Dean, D Chaudhry, L Ross, F Solari, S Chatterji, B Barmayehvar, S Lourenco, L Onos, F Mansour, A Radhakrishnan, M Varcada, M Richmond, I Hernández, A Spinelli, H Pham, J Shalhoub, F Wells, K Bevan, A Peckham-Cooper, N Campain, J Steinke, R Wilkin, K McEvoy, S Mastoridis, N Fine, J Bayer, Y Joshi, A Yener, S C McKay, NS Kalson, S Horvath, H Fu, A Parente, SE Lewis, Y Ahmad, G Seidel, M Dunstan, U von Oppell, J Vatish, H Hirsch, K Breen, C Dott, D Mathieu, J Hardie, K Aldridge, A Doorgakant, P Petrone, R Tansey, M El Amrani, C Branco, Y Viswanath, A Meagher, B Keeler, N Tewari, A Gabr, J Kinross, M Longhi, E M Harrison, P Daliya, P Asaad, F Langlands, N Misra, S Kristinsson, S Di Saverio, C Conso, H Roy, E Massie, L Masterson, D Baskaran, A Hannah, O Ismail, S URBAN, J Domenech, S Ranjit, L Massey, S Mannan, D Rutherford, F Colombo, R Kulkarni, D Kearney, Neil J Smart, G Bourke, D Shrestha, P Nankivell, O Breik, R Exley, D Zakai, AK Abou-Foul, P Naredla, R Vidya, G Mundy, H Marin, A E Ward, A Sudarsanam, W Singleton, M Ganau, F Moura, J Blanco, R Myatt, S Sousa, H Zahid, S Garrido, A Fell, E Caruana, D Nepogodiev, F Dhaif, B Bankhad-Kendall, H Kaafarani, C Bretherton, L Marais, K Siaw-Acheampong, B E Dawson, J C Glasbey, R R Gujjuri, E Heritage, S K Kamarajah, J M Keatley, S Lawday, G Pellino, J F F Simoes, I M Trout, M L Venn, R J W Wilkin, A O Ademuyiwa, E Al Ameer, O Alser, K M Augestad, B Bankhead-Kendall, R A Benson, S Chakrabortee, R Blanco-Colino, A Brar, A Minaya Bravo, K A Breen, I Lima Buarque, M F Cunha, G H Davidson, S Farik, M Fiore, G M A Gomes, C Halkias, I Lawani, H Lederhuber, S Leventoglu, M W Loffler, H Mashbari, D Mazingi, D Moszkowicz, J S Ng-Kamstra, S Metallidis, M Niquen, F Ntirenganya, O Outani, F Pata, T D Pinkney, P Pockney, D Radenkovic, A Ramos-De la Medina, A Schnitzbauer, S Shu, K Soreide, S Tabiri, P Townend, G Tsoulfas, G van Ramshorst, Mak JKC, F Tirotta, A Kisiel, LD Cato, AM Pathanki, A Chebaro, K Lecolle, S Truant, FR Pruvot, E Surmei, L Mattei, J Dudek, S El-Hasani, J Cuschieri, GH Davidson, RG Wade, H Elkadi, C Pompili, JR Burke, E Bagouri, Z Abual-Rub, S Munot, M Kowal, SC Winter, F Di Chiara, K Wallwork, A Qureishi, M Lami, S Sravanam, S Chidambaram, R Smillie, AV Shaw, C Cernei, D Jeyaretna, RJ Piper, E Duck, C Jelley, SC Tucker, G Bond-Smith, XL Griffin, GD Tebala, N Neal, TM Noton, H Ghattaura, OBF Risk, H Kharkar, C Verberne, A Senent-Boza, A Sánchez-Arteaga, I Benítez-Linero, F Manresa-Manresa, L Tallón-Aguilar, L Melero-Cortés, MR Fernández-Marín, VM Durán-Muñoz-Cruzado, I Ramallo-Solís, P Beltrán-Miranda, F Pareja-Ciuró, BT Antón-Eguía, AC Dawson, A Drane, F Oliva Mompean, J Gomez-Rosado, J Reguera-Rosal, J Valdes-Hernandez, L Capitan-Morales, del Toro Lopez, A Alanbuki, O Usman, AJ Beamish, D Bosanquet, D Magowan, H Nassa, G Mccabe, D Holroyd, NB Jamieson, NM Mariani, V Nicastro, D Motter, C Jenvey, T Minto, DR Sarma, C Godbole, W Carlos, A Khajuria, H Connolly, G Di Taranto, S Shanbhag, J Skillman, M Sait, H Al-omishy, B Heer, R Lunevicius, ARG Sheel, M Sundhu, AJA Santini, Fathelbab MSAT, KMA Hussein, QM Nunes, K Shahzad, Baig MMAS, JL Hughes, A Kattakayam, SB Shah, AL Clynch, N Georgopoulou, HM Sharples, AA Apampa, IC Nzenwa, D Podolsky, NL Coleman, MP Callahan, P Beak, I Gerogiannis, A Ebrahim, A Alwadiya, C Demetriou, E Grimley, E Theophilidou, E Ogden, FL Malcolm, G Davies-Jones, Ng JCK, N Elmaleh, Z Chia, J A'Court, A Konarski, R Talwar, P S Jambulingam, A Maity, C Hatzantonis, S Kudchadkar, N Cirocchi, CH Chan, H Eberbach, B Erdle, R Sandkamp, G Velmahos, LR Maurer, M El Moheb, A Gaitanidis, L Naar, MA Christensen, C Kapoen, K Langeveld, M El Hechi, B Main, T Maccabe, NS Blencowe, DP Fudulu, D Bhojwani, M Baquedano, F Rapetto, O Flannery, D Tadross, C Blundell, S Forlani, S Guha, CJ Kelty, G Chetty, G Lye, SP Balasubramanian, N Sureshkumar Shah, A Al-mukhtar, E Whitehall, A Giblin, A Adamec, J Konsten, M Van Heinsbergen, A Sou, J Jimeno Fraile, D Morales-Garcia, M Carrillo-Rivas, E Toledo Martínez, Pascual À, A Landaluce-olavarria, M Gonzalez De miguel, Fernández Gómez Cruzado L, E Begoña, D Lecumberri, A Calvo Rey, GM Prada hervella, L Dos Santos Carregal, MI Rodriguez Fernandez, M Freijeiro, S El Drubi Vega, J Van den Eynde, W Oosterlinck, R Van den Eynde, A Boeckxstaens, A Cordonnier, J Jaekers, M Miserez, M Galipienso Eri, JD Garcia Montesino, J Dellonder Frigolé, D Noriego Muñoz, V Lizzi, F Vovola, A Arminio, A Cotoia, AL Sarni, M Bekheit, BS Kamera, M Elhusseini, A Ahmeidat, W Cymes, G Mignot, J Agilinko, A Sgrò, MM Rashid, K Milne, KE Stewart, MSJ Wilson, K McGivern, BC Brown, B Wadham, IA Aneke, J Collis, H Warburton, DM Fountain, R Laurente, KV Sigamoney, M Dasa, Z Naqui, M Galhoum, MT Hasan, R Kalenderov, O Pathmanaban, R Chelva, K Subba, M Khalefa, F Hossain, T Moores, J Anthoney, O Emmerson, R Makin-Taylor, CS Ong, R Callan, O Bloom, G Chauhan, J Kaur, A Burahee, S Bleibleh, N Pigadas, D Snee, S Bhasin, A Crichton, A Habeebullah, AS Bodla, M Mondragon, V Dewan, MC Giuffrida, A Marano, S Palagi, S Di Maria Grimaldi, A Simonato, M D'Agruma, R Chiarpenello, L Pellegrino, F Maione, D Cianflocca, Pruiti Ciarello, G Giraudo, E Gelarda, E Dalmasso, A Abrate, V Ciriello, F Rosato, A Garnero, L Leotta, M Chiozza, G Anania, A Urbani, M Koleva Radica, P Carcoforo, M Portinari, M Sibilla, JE Archer, A Odeh, N Siddaiah, H Carmichael, CG Velopulos, RC McIntyre, TJ Schroeppel, EA Hennessy, L Zier, C Parmar, JM Muñoz Vives, CJ Gómez Díaz, CA Guariglia, C Soto Montesinos, L Sanchon, M Xicola Martínez, N Guàrdia, P Collera, R Diaz Del Gobbo, R Sanchez Jimenez, R Farre Font, R Flores Clotet, CEM Brathwaite, H Hakmi, AH Sohail, R Heckburn, D Townshend, N McLarty, A Shenfine, K Madhvani, M Hampton, AP Hormis, V Miu, K Sheridan, C Luney, MA Williams, A Alqallaf, A Ben-Sassi, R Crichton, J Sonksen, GR Layton, B Karki, S Pankhania, S Asher, A Folorunso, J Winyard, J Mangwani, BHB Babu, C Weerasinghe, M Ballabio, P Bisagni, T Armao, M Madonini, A Gagliano, P Pizzini, A Älgå, M Nordberg, G Sandblom, J El Kafsi, K Logishetty, A Saadya, R Midha, H Subbiah Ponniah, T Stockdale, T Bacarese-Hamilton, N Anjarwalla, D Marujo Henriques, R Hettige, C Baban, A Tenovici, F Anazor, SD King, S Kazzaz, S HKruijff, De Vries JPPM, PJ Steinkamp, PKC Jonker, WY Van der Plas, W Bierman, Y Janssen, ABJ Borgstein, D Enjuto, M Perez Gonzalez, P Díaz Peña, M Marqueta De Salas, P Martinez Pascual, L Rodríguez Gómez, R Garcés García, A Ramos Bonilla, N Herrera-Merino, P Fernández Bernabé, EP Cagigal Ortega, García de Castro Rubio E, I Cervera, MH Siddique, C Barmpagianni, A Basgaran, A Basha, V Okechukwu, A Bartsch, CA Leo, HK Ubhi, N Zafar, H Abdul-Jabar, F Mongelli, M Bernasconi, M Di Giuseppe, D Christoforidis, D La Regina, M Arigoni, A Al-Sukaini, S Mediratta, O Brown, M Boal, S Stanger, H Abdalaziz, J Constable, G Dovell, R Gopi reddy, A Dehal, HB Shah, GWV Cross, P Seyed-Safi, YW Smart, A Kuc, M Al-Yaseen, B Jayasankar, D Balasubramaniam, K Abdelsaid, N Mundkur, RE Soulsby, O Ryska, T Raymond, P Hawkin, G Kinnaman, I Sharma, K Freystaetter, JN Hadfield, A Hilley, S Arkani, M Youssef, I Shaikh, K Seebah, V Kouritas, D Chrastek, G Maryan, DF Gill, F Khatun, J Parakh, V Sarodaya, A Daadipour, KD Bosch, V Bashkirova, LS Dvorkin, VK Kalidindi, A Choudhry, M Espino Segura-Illa, G Sánchez Aniceto, AM Castaño-Leon, L Jimenez-Roldan, J Delgado Fernandez, A Pérez Núñez, A Lagares, D Garcia Perez, M Santas, I Paredes, O Esteban Sinovas, L Moreno-Gomez, E Rubio, V Vega, A Vivas Lopez, M Labalde Martinez, O García Villar, PM Pelaéz Torres, J Garcia Borda, E Ferrero Herrero, C Eiriz Fernandez, C Ojeda-Thies, JM Pardo Garcia, H Wynn Jones, H Divecha, C Whelton, E Powell-Smith, M Alotaibi, A Maashi, A Zowgar, M Alsakkaf, O Izquierdo, D Ventura, D Escobar, U Garcia de cortazar, Villamor Garcia, A Cioci, K Rakoczy, W Pavlis, R Saberi, A Khaleel, A Unnithan, K Memon, RR Pala Bhaskar, F Maqboul, F Kamel, A Al-Samaraee, R Madani, H Llaquet Bayo, N Duchateau, C De Gheldere, A Fayad, ML Wood, G Groot, I Hakami, C Boeker, J Mall, AF Haugstvedt, ML Jönsson, P Caja Vivancos, Villalabeitia Ateca, M Prieto Calvo, P Martin Playa, A Gainza, EJ Aragon Achig, A Rodriguez Fraga, Melchor Corcóstegui, G Mallabiabarrena Ormaechea, JJ Garcia Gutierrez, L Barbier, MA Pesántez Peralta, M Jiménez Jiménez, JA Municio Martín, J Gómez Suárez, G García Operé, LA Pascua Gómez, M Oñate Aguirre, A Fernandez-Colorado, M De la Rosa-Estadella, A Gasulla-Rodriguez, M Serrano-Martin, A Peig-Font, S Junca-Marti, M Juarez-Pomes, S Garrido-Ondono, L Blasco-Torres, M Molina-Corbacho, Y Maldonado-Sotoca, A Gasset-Teixidor, J Blasco-Moreu, V Turrado-Rodriguez, AM Lacy, FB de Lacy, X Morales, A Carreras-Castañer, P Torner, M Jornet-Gibert, M Balaguer-Castro, M Renau-Cerrillo, P Camacho-Carrasco, M Vives-Barquiel, B Campuzano-Bitterling, I Gracia, R Pujol-Muncunill, M Estaire Gómez, D Padilla-Valverde, S Sánchez-García, D Sanchez-Pelaez, E Jimenez Higuera, R Picón Rodríguez, Fernández Camuñas À, C Martínez-Pinedo, EP Garcia Santos, V Muñoz-Atienza, A Moreno Pérez, CA Cano, D Crego-Vita, M Huecas-Martinez, A Roselló Añón, MJ Sangüesa, JC Bernal-Sprekelsen, JC Catalá Bauset, P Renovell Ferrer, C Martínez Pérez, O Gil-Albarova, J Gilabert Estellés, K Aghababyan, R Rivas, J Escartin, JL Blas Laina, B Cros, Talal El-Abur, J Garcia Egea, C Yanez, JH Kauppila, E Sarjanoja, S Tzedakis, PA Bouche, S Gaujoux, D Gossot, A Seguin-Givelet, D Fuks, M Grigoroiu, R Sanchez Salas, X Cathelineau, P Macek, Y Barbé, F Rozet, E Barret, A Mombet, N Cathala, E Brian, F Zadegan, AJ Baldwin, E Gammeri, A Catton, S Marinos Kouris, J Pereca, M Kaushal, A Kler, V Reghuram, S Tezas, V Oktseloglou, F Mosley, MFI De La Cruz Monroy, P Bobak, S Ahad, E Lostis, GK Ambler, J Manara, M Doe, T Jichi, GD Stewart, J Ramzi, AA Singh, J Ashcroft, OJ Baker, P Coughlin, Durst AZED, A Abood, A Habeeb, VE Hudson, B Lamb, L Luke, S Mitrasinovic, Ngu AWT, S Waseem, F Georgiades, XS Tan, J Pushpa-rajah, I Abu-Nayla, S Rooney, E Irune, MHV Byrne, A Durrani, A Sethuraman Venkatesan, T Combellack, G Tahhan, M Kornaszewska, V Valtzoglou, I Deglurkar, M Koutentakis, Syed Nong Chek SAH, M Shinkwin, F Ayeni, H Tustin, M Bordenave, N Manu, N Eardley, OL Serevina, S Roy Mahapatra, K Mohankumar, I Khawaja, A Palepa, T Doulias, Y Premakumar, Y Jauhari, Z Koshnow, A Uberai, F Hirri, BM Stubbs, J Manickavasagam, S Dalgleish, R Kanitkar, CJ Payne, Ng CE, DE Henshall, T Drake, EM Harrison, A Tambyraja, RJE Skipworth, G Linder, R McGregor, J Mayes, R Pasricha, A Razik, S Thrumurthy, D Howden, Z Baxter, L Osagie, M Bence, GE Fowler, N Rajaretnam, A Goubran, JS McGrath, JRA Phillips, DA Raptis, JM Pollok, F Soggiu, S Xyda, C Hidalgo Salinas, H Tzerbinis, T Pissanou, R Mirnezami, N Angamuthu, T Shakir, H Capitelli-McMahon, L Hitchman, A Andronic, A Aboelkassem Ibrahim, J Totty, S Tayeh, T Chase, J Ayorinde, T Cuming, A Trompeter, C Hing, P Tsinaslanidis, MW Benjamin, A Leyte, J Smelt, G Santhirakumaran, A Labib, O Lyons, S Onida, KM Sarraf, S Erridge, S Yalamanchili, A Abuown, D Davenport, S Wheatstone, SM Andreani, MF Bath, A Sahni, L Rigueros Springford, C Sohrabi, J Bacarese-Hamilton, FG Taylor, P Patki, C Tanabalan, ME Alexander, CJ Smart, L Abdeh, M Zeiton, R Advani, S Nikolaou, T Oni, N Ilahi, K Ballantyne, Z Woodward, R Merh, B Robertson-Smith, P Ameerally, JG Finch, C Gnanachandran, I Pop, D Dass, G Thiruchandran, Toh SKC, A Allana, C Bellis, O Babawale, YC Phan, U Lokman, T Koc, L Duggleby, S Shamoon, H Clancy, A Mansuri, A Thakrar, L Wickramarachchi, S Sivayoganathan, E Karam, HV Colvin, A Badran, A Cadersa, A Cumpstey, R Aftab, F Wensley, V Morrison-Jones, GK Sekhon, H Shields, Z Shakoor, T Talbot, A Alzetani, J Rooney, M Rudic, A Aladeojebi, M Kitchen, R Lefroy, P Nanjaiah, AD Rajgor, RJ Scurrah, LJ Watson, T Royle, B Steel, Luk ACO, VG Thiruvasagam, W Marlow, C Konstantinou, D Yershov, A Denning, E Mangos, T Nambirajan, I Flindall, V Mahendran, J De Marchi, NF Davis, A Picciariello, V Papagni, DF Altomare, S Granieri, C Cotsoglou, A Cabeleira, P Serralheiro, T Teles, C Canhoto, J Simões, AC Almeida, O Nogueira, R Athayde Nemésio, MJ Amaral, A Valente da Costa, R Martins, P Guerreiro, A Ruivo, D Breda, JM Oliveira, AL De Oliveira Lopez, M Colino, J De Barros, AP Soares, H Morais, T Revez, MI Manso, JC Domingues, P Henriques, Cardoso N Ribeiro VI, G Martins dos Santos, M Peralta Ferreira, J Ascensão, B Costeira, L Rio Rodrigues, M Sousa Fernandes, P Azevedo, I Lourenço, G Mendinhos, A Nobre Pinto, H Taflin, H Abdou, L O'Meara, Z Cooper, SA Hirji, BU Okafor, V Roxo, CP Raut, JS Jolissaint, DA Mahvi, C Reinke, S Merola, A Ssentongo, P Ssentongo, Oh JS, J Hazelton, J Maines, N Gusani, RCG Martin, N Bhutiani, R Choron, F Soliman, MD E Dauer, E Renza-Stingone, E Gokcen, E Kropf, H Sufrin, J Sewards, J Poggio, K Sanserino, L Rae, M Philp, M Metro, P McNelis, R Petrov, T Pazionis, DB Lumenta, SP Nischwitz, E Richtig, M Pau, P Srekl-Filzmaier, N Eibinger, B Michelitsch, M Fediuk, A Papinutti, TU Cohnert, E Kantor, J Kahiu, S Hosny, A Sultana, M Taggarsi, L Vitone, OP Vaz, I Sarantitis, S Timbrell, A Shugaba, GP Jones, SS Tripathi, MS Greenhalgh, H Emerson, K Vejsbjerg, W McCormick, K Singisetti, Y Aawsaj, R Vanker, M Ghobrial, S Kanthasamy, H Fawi, M Awadallah, J Cheung, S Tingle, F Abbadessa, A Sachdeva, CD Chan, I McPherson, F Mahmoud Ali, S Pandanaboyana, T Grainger, S Nandhra, N Dawe, C McCaffer, J Riches, J Moir, H Elamin Ahmed, C Saleh, RM Koshy, LJ Rogers, PL Labib, N Hope, K Emslie, P Panahi, E Clough, I Enemosah, J Natale, N Raza, JI Webb, M Antar, J Noel, R Nunn, F Eriberto, R Tanna, S Lodhia, C Osório, J Antunes, P Balau, and M Godinho
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Medicine - Abstract
Objectives Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.Setting Prospective, international, multicentre, observational cohort study.Participants Patients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome 30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.Results This study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).Conclusions Patients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration number NCT04323644
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- 2021
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4. The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between Subtypes
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Catherine M. Olsen, Ian B. Hickie, Nicholas G. Martin, Naomi R. Wray, Adrian I. Campos, Brittany L. Mitchell, Scott D. Gordon, Enda M. Byrne, Sarah E. Medland, Adam J. Walker, Michael Berk, Olivia M Dean, and David C. Whiteman
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Genetics ,Depressive Disorder, Major ,Multifactorial Inheritance ,Depression ,business.industry ,Genetic heterogeneity ,Australia ,Genome-wide association study ,medicine.disease ,Polymorphism, Single Nucleotide ,Mental health ,Genetic etiology ,Cohort ,medicine ,Humans ,Major depressive disorder ,Genetic Predisposition to Disease ,Age of onset ,business ,Biological Psychiatry ,Depression (differential diagnoses) ,Genome-Wide Association Study - Abstract
Background Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder but little is known about the genetic characterisation of this heterogeneity. Understanding the genetic etiology of MDD can be challenging as large sample sizes are needed for gene discovery – often achieved with a trade-off in the depth phenotyping. Methods The Australian Genetics of Depression Study is the largest stand-alone depression cohort with both genetic data and in-depth phenotyping and comprises a total of 15,792 participants of European ancestry, 92% of whom, met diagnostic criteria for MDD. We leveraged the unique nature of this cohort to conduct a meta-analysis with the largest depression GWAS to date and subsequently used polygenic scores (PGS) to investigate genetic heterogeneity across various clinical subtypes of MDD. Results We increased the number of known genome-wide significant variants associated with depression from 103 to 126 and found evidence of association of novel genes implicated in neuronal development. We show that a PGS for depression explains 5.7% of variance in MDD liability in our sample. Lastly, we find strong support for genetic heterogeneity in depression with differential associations of multiple psychiatric and comorbid traits with age of onset, longitudinal course and various subtypes of MDD. Conclusions Until now, this degree of detailed phenotyping in such a large sample of MDD cases has not been possible. Along with discovery of novel loci, we provide support for differential pathways to illness models that recognize both the overlap with other common psychiatric disorders, as well as pathophysiological differences.
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- 2022
5. Radiology Stereotypes, Application Barriers, and Hospital Integration: A Mixed-methods Study of Medical Student Perceptions of Radiology
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Charles M. Maxfield, Vesta C. Nwankwo, Caroline Carrico, Jonathan G. Martin, Laura J. Fish, Samantha Farley, Carolyn C. Meltzer, and Lars J. Grimm
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Student perceptions ,medicine.medical_specialty ,Students, Medical ,Coronavirus disease 2019 (COVID-19) ,media_common.quotation_subject ,COVID-19 ,Survey result ,Affect (psychology) ,Focus group ,Student education ,Hospitals ,Article ,Mentorship ,Artificial Intelligence ,Perception ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Radiology ,Psychology ,media_common - Abstract
Rationale and Objectives Limited exposure to radiology by medical students can perpetuate negative stereotypes and hamper recruitment efforts. The purpose of this study is to understand medical students’ perceptions of radiology and how they change based on medical education and exposure. Materials and Methods A single-institution mixed-methods study included four groups of medical students with different levels of radiology exposure. All participants completed a 16-item survey regarding demographics, opinions of radiology, and perception of radiology stereotypes. Ten focus groups were administered to probe perceptions of radiology. Focus groups were coded to identify specific themes in conjunction with the survey results. Results Forty-nine participants were included. Forty-two percent of participants had positive opinions of radiology. Multiple radiology stereotypes were identified, and false stereotypes were diminished with increased radiology exposure. Opinions of the impact of artificial intelligence on radiology closely aligned with positive or negative views of the field overall. Multiple barriers to applying for a radiology residency position were identified including board scores and lack of mentorship. COVID-19 did not affect perceptions of radiology. There was broad agreement that students do not enter medical school with many preconceived notions of radiology, but that subsequent exposure was generally positive. Exposure both solidified and eliminated various stereotypes. Finally, there was general agreement that radiology is integral to the health system with broad exposure on all services. Conclusion Medical student perceptions of radiology are notably influenced by exposure and radiology programs should take active steps to engage in medical student education.
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- 2022
6. Safety Profile of Particle Embolization for Treatment of Acute Lower Gastrointestinal Bleeding
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Charles Y. Kim, Rui Dai, Elisabeth R. Seyferth, Nicholas T. Befera, Alan A. Sag, Jonathan G. Martin, Waleska M. Pabon-Ramos, Paul V. Suhocki, Tony P. Smith, and James Ronald
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Male ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Angiography ,Colonoscopy ,Retrospective cohort study ,Bowel resection ,Embolization, Therapeutic ,Surgery ,Safety profile ,Acute lower gastrointestinal bleeding ,Treatment Outcome ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,In patient ,Embolization ,Gastrointestinal Hemorrhage ,Cardiology and Cardiovascular Medicine ,Adverse effect ,business ,Aged ,Retrospective Studies - Abstract
Purpose To assess ischemic adverse events following particle embolization when used as a second-line embolic to coil embolization for treatment of acute lower gastrointestinal bleeding(LGIB). Materials and Methods This single-institution retrospective study examined 154 procedures where embolization was attempted for LGIB. In 122 patients (64 males, mean age 69.9 years), embolization was successfully performed using microcoils in 73 procedures, particles in 34 procedures, and both microcoils and particles in 27 procedures. Particles were used as second-line only when coil embolization was infeasible or inadequate. Technical success was defined as angiographic cessation of active extravasation after embolization. Clinical success was defined as absence of recurrent bleeding within 30 days of embolization. Results Technical success for embolization of LGIB was achieved in 87.0% of cases (134/154), and clinical success was 76.1%(102/134) among technically successful cases. Clinical success was 82.2%(60/73) for coils alone and 68.9%(42/61) for particles +/- coils. Severe adverse events involving embolization-induced bowel ischemia occurred in 3 of 56 patients who underwent particle embolization +/- coils (5.3%) versus zero out of 66 patients when coils alone were used (P=0.09). In patients who had colonoscopy or bowel resection within 2 weeks of embolization, ischemic findings attributable to the embolization were found in 3 of 15 who underwent embolization with coils alone, versus 8 of 18 who underwent embolization with particles +/- coils (p=0.27). Conclusion Particle embolization for treatment of LGIB as second line to coil embolization was associated with a 68.9% clinical success rate and a 5.3% rate of ischemia-related adverse events.
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- 2022
7. Diagnostic accuracy of clinically reported adenomyosis on pelvic ultrasound and MRI compared to surgical pathology
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Jonathan G. Martin, Nicholas T. Befera, Nicole Zanolli, and Brendan Cline
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medicine.medical_specialty ,Pathology, Surgical ,medicine.medical_treatment ,Endometriosis ,Sensitivity and Specificity ,Surgical pathology ,Medical imaging ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Adenomyosis ,Ultrasonography ,Hysterectomy ,medicine.diagnostic_test ,business.industry ,Gynecologic pathology ,Ultrasound ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,body regions ,Diagnostic odds ratio ,Female ,Radiology ,business - Abstract
Background Adenomyosis is a common gynecologic pathology that relies on diagnostic imaging to guide treatment. Accuracy of both pelvic ultrasound and magnetic resonance imaging (MRI) when specifically evaluating for the presence of adenomyosis is high. However, the accuracy of reported rates in clinical practice is less well understood. Purpose To demonstrate the accuracy in reporting of adenomyosis on pelvic ultrasound and MRI compared to histopathology in common clinical practice. Basic procedures An institutional database was searched for women with a pelvic ultrasound and a pelvic MRI with a subsequent hysterectomy. Findings were extracted from radiology and pathology reports, and the documented presence or absence of adenomyosis was recorded for each modality. Blinded radiologists viewed each imaging pair to directly evaluate for adenomyosis. Main findings Compared to prior published data, imaging had lower accuracy in clinical practice when adenomyosis was not specifically evaluated for. For the finding of adenomyosis, pelvic ultrasound had a sensitivity of 10.9%, a specificity of 98.3%, positive predictive value (PPV) of 77.8%, negative predictive value (NPV) of 66.7%, an accuracy of 67.2%, and a diagnostic odds ratio (DOR) of 7. Pelvic MRI had a sensitivity of 29.7%, specificity of 85.3%, PPV of 52.8%, NPV of 68.8%, an accuracy of 65.6%, and DOR of 2.5. Overall accuracy of MRI improved when adenomyosis was directly evaluated for (82.4% vs 65.6%). Principle conclusions Without direct communication to evaluate for adenomyosis, pelvic ultrasound and MRI may underestimate or misreport adenomyosis. Providers should be aware of these discrepancies when relying on radiology reports to guide treatment and potential interventions when diagnosing and managing adenomyosis.
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- 2022
8. Quantifying the Financial Impact of Delayed Adoption of CPT Code Changes in Radiology
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Waleska M. Pabon-Ramos, Gabriel Li, Jan Taylor, and Jonathan G. Martin
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Current Procedural Terminology ,medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,Payment ,Radiography ,Vetting ,Radiologists ,Equating ,Humans ,Medicine ,Revenue ,Radiology, Nuclear Medicine and imaging ,Radiology ,business ,Root cause analysis ,Reimbursement ,media_common ,Coding (social sciences) - Abstract
Purpose To quantify the financial effect of delayed reporting of new moderate sedation (MS) Current Procedural Terminology (CPT) codes at an academic radiology practice, and to identify barriers to timely reporting. Materials and Methods Billing and reimbursement data was collected for a 28-month period (January 1, 2017-April 30, 2019). Reporting of new MS codes was identified and compared to the number of procedures performed by radiology over the study period. Using the number of procedures performed and payment data, losses were estimated. A root cause analysis was then performed to further understand delayed reporting. Results MS was reported with 2.5% of cases in 2017, 47.8% of cases in 2018 and 69.1% of cases in 2019. Appropriate coding was not achieved until June 2018, equating to a 17-month lag in implementation. Lost revenue from inaccurate reporting of MS alone was $21,357 ± $3,945 per month. Primary barriers to an efficient transition included (1) updating billing systems, (2-5) coder, nursing, technologist, and operator education and coordination, and (6) drafting and vetting new procedural report templates. Conclusions Delayed reporting of the new moderate sedation codes resulted in a $363,069 ± $67,065 loss of procedural revenue at an academic radiology practice. Primary drivers of the delay were lags in education and coordination at multiple points in the reporting chain. As healthcare policy shifts and changes to coding become more frequent and significant, timely adoption becomes more salient for radiologists.
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- 2022
9. Cortical thickness across the lifespan
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Simon E. Fisher, Eveline A. Crone, Dominik Grotegerd, Jilly Naaijen, Anders M. Dale, Sean N. Hatton, Ramona Baur-Streubel, Anthony A. James, Daniel Brandeis, Andrew J. Kalnin, Andreas Reif, Hans-Jörgen Grabe, Pieter J. Hoekstra, Lars Nyberg, Fleur M. Howells, Moji Aghajani, Randy L. Buckner, Daniel A. Rinker, Steven G. Potkin, Dennis van 't Ent, Rachel M. Brouwer, Sophia Frangou, Yang Wang, Nhat Trung Doan, Theodore D. Satterthwaite, Christine Lochner, Geraldo F. Busatto, Lars T. Westlye, Lara M. Wierenga, Calhoun Vd, Henry Brodaty, Carles Soriano-Mas, Annette Conzelmann, Christian K. Tamnes, Julian N. Trollor, Nicholas G. Martin, Neeltje E.M. van Haren, René S. Kahn, Irina Lebedeva, Philip Asherson, Suzanne C. Swagerman, John A. Joska, Theophilus N. Akudjedu, Kang Sim, Lachlan T. Strike, Patricia Gruner, Brenna C. McDonald, Thomas Frodl, Edith Pomarol-Clotet, Víctor Ortiz-García de la Foz, Margaret J. Wright, Norbert Hosten, Jean-Paul Fouche, Bernd Weber, Salvador Sarró, Wei Wen, Dag Alnæs, Greig I. de Zubicaray, Iris E. C. Sommer, Marise W. J. Machielsen, Knut Schnell, Dara M. Cannon, Paola Fuentes-Claramonte, Josiane Bourque, Andreas Meyer-Lindenberg, Anton Albajes-Eizagirre, Sarah Hohmann, Erin W. Dickie, Theo G.M. van Erp, Micael Andersson, Paul Pauli, Thomas Espeseth, Heather C. Whalley, Victoria Chubar, Ruben C. Gur, Tomohiro Nakao, Xavier Caseras, Alessandro Bertolino, Ignacio Martínez-Zalacaín, Katharina Wittfeld, Erick J. Canales-Rodríguez, David C. Glahn, Neda Jahanshad, Jiyang Jiang, Katie L. McMahon, Stefan Borgwardt, Erlend S. Dørum, Jaap Oosterlaan, Won Hee Lee, Alan Breier, Steven Williams, Aristotle N. Voineskos, Bernard Mazoyer, Jordan W. Smoller, Nancy C. Andreasen, Ilya M. Veer, Tiffany M. Chaim-Avancini, Sophie Maingault, Paul M. Thompson, Eco J. C. de Geus, Luisa Lázaro, Giulio Pergola, Efstathios Papachristou, Beng-Choon Ho, David Mataix-Cols, Esther Walton, Ben J. Harrison, Dirk J. Heslenfeld, Pablo Najt, Helena Fatouros-Bergman, Derrek P. Hibar, Gunter Schumann, Raymond Salvador, Lieuwe de Haan, Henry Völzke, Joaquim Radua, Henk Temmingh, Lianne Schmaal, Martine Hoogman, Daniel H. Wolf, Georg C. Ziegler, Marieke Klein, Barbara Franke, Erik G. Jönsson, Laura Koenders, Stefan Ehrlich, Oliver Gruber, Ingrid Agartz, Kun Yang, Ryota Kanai, Sarah Baumeister, Colm McDonald, Annabella Di Giorgio, Amanda Worker, Anne Uhlmann, Marcus V. Zanetti, Danai Dima, Matthew D. Sacchet, Sarah E. Medland, Aurora Bonvino, Benedicto Crespo-Facorro, Jan Egil Nordvik, Joshua L. Roffman, Yannis Paloyelis, Jessica A. Turner, T. P. Klyushnik, Christopher G. Davey, Rachel E. Gur, Ian B. Hickie, Christopher R.K. Ching, Jonna Kuntsi, Tobias Banaschewski, Chaim Huyser, Amirhossein Modabbernia, John D. West, Fabrice Crivello, Núria Bargalló, Patricia J. Conrod, Nic J.A. van der Wee, Mauricio H. Serpa, Thomas H. Wassink, Kathryn I. Alpert, Dick J. Veltman, Andrew J. Saykin, Genevieve McPhilemy, Perminder S. Sachdev, Vincent P. Clark, Ian H. Gotlib, Susanne Erk, Henrik Walter, Dennis van den Meer, Simon Cervenka, Oliver Grimm, Andrew M. McIntosh, Alexander Tomyshev, Francisco X. Castellanos, Bernd Kramer, Klaus-Peter Lesch, Odile A. van den Heuvel, Sophia I. Thomopoulos, Diana Tordesillas-Gutiérrez, Terry L. Jernigan, Yulyia Yoncheva, Anouk den Braber, Jim Lagopoulos, Maria J. Portella, Ole A. Andreassen, Gaelle E. Doucet, Avram J. Holmes, Nynke A. Groenewold, Pedro G.P. Rosa, Hilleke E. Hulshoff Pol, Sanne Koops, José M. Menchón, Jan K. Buitelaar, Dan J. Stein, Dorret I. Boomsma, Lei Wang, C.A. Hartman, Pascual Sánchez-Juan, Andreas Heinz, European Commission, National Institute of Child Health and Human Development (US), QIMR Berghofer Medical Research Institute (Australia), University of Queensland, National Cancer Institute (US), Dutch Research Council, Netherlands Organisation for Health Research and Development, National Institute of Mental Health (US), European Research Council, National Center for Advancing Translational Sciences (US), Medical Research Council (UK), Fundación Marques de Valdecilla, Instituto de Salud Carlos III, Swedish Research Council, South-Eastern Norway Regional Health Authority, Research Council of Norway, Icahn School of Medicine at Mount Sinai, South London and Maudsley NHS Foundation Trust, NHS Foundation Trust, National Institute for Health Research (UK), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Movement Disorder (MD), Developmental Neuroscience in Society, Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Child Psychiatry, ANS - Cellular & Molecular Mechanisms, General Paediatrics, ARD - Amsterdam Reproduction and Development, Karolinska Schizophrenia Project (KaSP), Ontwikkelingspsychologie (Psychologie, FMG), Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Epidemiology and Data Science, Neurology, Amsterdam Neuroscience - Neurodegeneration, Pediatric surgery, Anatomy and neurosciences, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Brain Imaging, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Biological Psychology, APH - Methodology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Educational and Family Studies, Cognitive Psychology, IBBA, Clinical Neuropsychology, Faculty of Behavioural and Movement Sciences, and APH - Personalized Medicine
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Male ,Aging ,Neurologi ,Audiology ,Trajectories ,0302 clinical medicine ,130 000 Cognitive Neurology & Memory ,diagnostic imaging [Cerebral Cortex] ,Child ,Research Articles ,Cerebral Cortex ,Psychiatry ,Aged, 80 and over ,Radiological and Ultrasound Technology ,Fractional polynomial ,05 social sciences ,Radiology, Nuclear Medicine & Medical Imaging ,1. No poverty ,Cognition ,Middle Aged ,Cerebral cortex ,Regression ,3. Good health ,Escorça cerebral ,Neurology ,Radiology Nuclear Medicine and imaging ,Healthy individuals ,Child, Preschool ,anatomy & histology [Cerebral Cortex] ,Female ,Analysis of variance ,Anatomy ,Life Sciences & Biomedicine ,Trajectorie ,Research Article ,Neuroinformatics ,Adult ,medicine.medical_specialty ,Adolescent ,Human Development ,Clinical Neurology ,BF ,Neuroimaging ,Biology ,Development ,050105 experimental psychology ,Psykiatri ,Cortical thickness ,03 medical and health sciences ,Young Adult ,Neuroimaging genetics ,Envelliment ,medicine ,Humans ,trajectories ,0501 psychology and cognitive sciences ,Radiology, Nuclear Medicine and imaging ,ddc:610 ,development ,Aged ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Science & Technology ,Brain morphometry ,aging ,Neurosciences ,cortical thickness ,Cross-Sectional Studies ,RC0321 ,Neurology (clinical) ,Neurosciences & Neurology ,030217 neurology & neurosurgery ,physiology [Human Development] - Abstract
Special Issue: The ENIGMA Consortium: the first 10 years., Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes., European Community's Seventh Framework Programme, Grant/Award Numbers: 278948, 602450, 603016, 602805; US National Institute of Child Health and Human Development, Grant/Award Numbers: RO1HD050735, 1009064, 496682; QIMR Berghofer Medical Research Institute and the Centre for Advanced Imaging, University of Queensland; ICTSI NIH/NCRR, Grant/Award Number: RR025761; European Community's Horizon 2020 Programme, Grant/Award Numbers: 667302, 643051; Vici Innovation Program, Grant/Award Numbers: #91619115, 016-130-669; NWO Brain & Cognition Excellence Program, Grant/Award Number: 433-09-229; Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL); Spinozapremie, Grant/Award Number: NWO-56-464-14192; Biobanking and Biomolecular Resources Research Infrastructure, Grant/Award Numbers: 184.033.111, 184.021.007; Netherlands Organization for Health Research and Development (ZonMW), Grant/Award Numbers: 480-15-001/674, 024.001.003, 911-09-032, 056-32-010, 481-08-011, 016-115-035, 31160008, 400-07-080, 400-05-717, 451-04-034, 463-06-001, 480-04-004, 904-61-193, 912-10-020, 985-10-002, 904-61-090; NIMH, Grant/Award Number: R01 MH090553; Geestkracht programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Numbers: NWO/SPI 56-464-14192, NWO-MagW 480-04-004, 433-09-220, NWO 51.02.062, NWO 51.02.061; National Center for Advancing Translational Sciences, National Institutes of Health, Grant/Award Number: UL1 TR000153; National Center for Research Resources; National Center for Research Resources at the National Institutes of Health, Grant/Award Numbers: NIH 1U24 RR025736-01, NIH 1U24 RR021992; NIH Institutes contributing to the Big Data to Knowledge; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Numbers: U54EB020403, G0500092; National Institute of Mental Health, Grant/Award Numbers: R01MH117014, R01MH042191; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; Swedish Research Council, Grant/Award Numbers: 523-2014-3467, 2017-00949, 521-2014-3487; South-Eastern Norway Health Authority; the Research Council of Norway, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Icahn School of Medicine at Mount Sinai; Seventh Framework Programme (FP7/2007-2013), Grant/Award Number: 602450; National Institutes of Health, Grant/Award Numbers: R01 MH116147, R01 MH113619, R01 MH104284; South London and Maudsley NHS Foundation Trust; the National Institute for Health Research (NIHR)
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- 2022
10. Greater male than female variability in regional brain structure across the lifespan
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Erick J. Canales-Rodríguez, Hans J. Grabe, Dirk J. Heslenfeld, Erik G. Jönsson, Oliver Gruber, Daniel Brandeis, Yang Wang, Henry Brodaty, Ruben C. Gur, Iris E. C. Sommer, Paul M. Thompson, Knut K. Kolskår, Christopher G. Davey, Dick J. Veltman, Eco J. C. de Geus, Tobias Banaschewski, Greig I. Zubicaray, Xavier Caseras, Sarah Baumeister, Raquel E. Gur, Vincent P. Clark, Maria J. Portella, Simon E. Fisher, Christopher R.K. Ching, Lars T. Westlye, Laura Koenders, Vince D. Calhoun, Carles Soriano-Mas, Nicholas G. Martin, Stefan Ehrlich, Fleur M. Howells, Catharina A. Hartman, Matthew D. Sacchet, Ole A. Andreassen, Josiane Bourque, Fabrice Crivello, Annette Conzelmann, Jaap Oosterlaan, Brenna C. McDonald, Gaelle E. Doucet, Avram J. Holmes, José M. Menchón, Danai Dima, Moji Aghajani, Joshua L. Roffman, Steven Williams, Lei Wang, David Mataix-Cols, Philip R. Szeszko, Bernd Weber, Tiril P. Gurholt, Sarah Hohmann, Ian H. Gotlib, Patricia Gruner, Anthony C. James, Paul Pauli, Lara M. Wierenga, Andrew M. McIntosh, Andrew J. Kalnin, Jim Lagopoulos, Henrik Walter, Andreas Reif, Andrew Simmons, Norbert Hosten, Pieter J. Hoekstra, Aristotle Voineskos, Alexander Tomyshev, Anton Albajes-Eizagirre, Jean-Paul Fouche, Dara M. Cannon, Ignacio Martínez‐Zalacaín, Geneviève Richard, Theophilus N. Akudjedu, David C. Glahn, Patricia J. Conrod, Ben J. Harrison, Alan Anticevic, Martine Hoogman, Francisco X. Castellanos, Bernd Kramer, Neda Jahanshad, Lieuwe de Haan, Dennis van der Meer, John D. West, Alan Breier, Jordan W. Smoller, P. G. P. Rosa, Katharina Wittfeld, Dan J. Stein, Jiyang Jiang, Jilly Naaijen, Christine Lochner, Dorret I. Boomsma, Alessandro Bertolino, Marise W. J. Machielsen, Hilleke E. Hulshoff Pol, Henry Völzke, Christian K. Tamnes, Ingrid Agartz, Georg C. Ziegler, Marieke Klein, Lars Nyberg, Perminder S. Sachdev, Philip Asherson, I.M. Veer, Sean N. Hatton, Núria Bargalló, Annabella Di Giorgio, Henk Temmingh, John A. Joska, Odile A. van den Heuvel, Wei Wen, Eveline A Crone, Kang Sim, Kathryn I. Alpert, Dennis van 't Ent, Jan K. Buitelaar, Joaquim Radua, Julian N. Trollor, B Mazoyer, Chaim Huyser, H. C. Whalley, Irina Lebedeva, Erin W. Dickie, Marcus Vinicus Zanetti, Stefan Borgwardt, Theodore D. Satterthwaite, Daniel H Wolf, Sophia I. Thomopoulos, Giulio Pergola, Luisa Lazaro, Ramona Baur-Streubel, Beathe Haatveit, Yannis Paloyelis, Ian B. Hickie, Jonna Kuntsi, Sophia Frangou, R. Salvador, Geraldo F. Busatto, Margaret J. Wright, Aurora Bonvino, Edith Pomarol-Clotet, Anouk den Braber, Lachlan T. Strike, Phil Lee, Anne Uhlmann, Yuliya N. Yoncheva, Mauricio H. Serpa, Dag Alnæs, Paola Fuentes-Claramonte, Katie L. McMahon, Andrew J. Saykin, Genevieve McPhilemy, Tiffany M. Chaim-Avancini, Sophie Maingault, Barbara Franke, Colm McDonald, Rachel M. Brouwer, Salvador Sarró, Department of Psychology, Education and Child Studies, Biological Psychology, APH - Mental Health, APH - Methodology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, AMS - Ageing & Vitality, AMS - Sports, APH - Personalized Medicine, Cognitive Psychology, Clinical Neuropsychology, IBBA, Karolinska Schizophrenia Project (KaSP) Consortium, Adult Psychiatry, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Child Psychiatry, ANS - Cellular & Molecular Mechanisms, ANS - Amsterdam Neuroscience, General Paediatrics, ARD - Amsterdam Reproduction and Development, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Movement Disorder (MD), Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Neurology, Amsterdam Neuroscience - Neurodegeneration, Anatomy and neurosciences, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Pediatric surgery, and Amsterdam Neuroscience - Brain Imaging
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Male ,Netherlands Twin Register (NTR) ,SEGMENTATION ,Vulnerability ,Disease ,HM ,0302 clinical medicine ,Anàlisi de variància ,130 000 Cognitive Neurology & Memory ,diagnostic imaging [Cerebral Cortex] ,sexual characteristics ,Analysis of variance ,nuclear magnetic resonance imaging ,Cervell ,Research Articles ,Cerebral Cortex ,Sex Characteristics ,Radiological and Ultrasound Technology ,05 social sciences ,Brain ,clinical trial ,Brain Structure ,Magnetic Resonance Imaging ,Early life ,Adolescence ,medicine.anatomical_structure ,Neurology ,Cerebral cortex ,Healthy individuals ,X-CHROMOSOME ,anatomy & histology [Cerebral Cortex] ,Evolution of the brain ,Female ,Anatomy ,Neurovetenskaper ,Research Article ,Radiology, Nuclear Medicine and Medical Imaging ,Neuroinformatics ,SEX-DIFFERENCES ,diagnostic imaging ,brain ,Human Development ,BF ,Neuroimaging ,SURFACE-AREA ,Evolució del cervell ,Regional area ,Biology ,MULTISAMPLE ,050105 experimental psychology ,brain cortex ,03 medical and health sciences ,CEREBRAL-CORTEX ,Sex differences ,medicine ,Humans ,0501 psychology and cognitive sciences ,Radiology, Nuclear Medicine and imaging ,human ,ddc:610 ,Cortical surface ,GENERAL INTELLIGENCE ,diagnostic imaging [Brain] ,METAANALYSIS ,biological variation ,HUMAN HIPPOCAMPUS ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,physiology [Biological Variation, Population] ,Neurosciences ,Gender ,Brain Cortical Thickness ,multicenter study ,Biological Variation, Population ,Diferències entre sexes ,physiology ,RC0321 ,Radiologi och bildbehandling ,Neurology (clinical) ,anatomy & histology [Brain] ,170 000 Motivational & Cognitive Control ,030217 neurology & neurosurgery ,anatomy and histology ,meta analysis ,physiology [Human Development] ,Demography - Abstract
Contains fulltext : 248376.pdf (Publisher’s version ) (Open Access) For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.
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- 2022
11. Macrophage activation syndrome-like (MAS-L) manifestations following BCMA-directed CAR T cells in multiple myeloma
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Jeffrey L. Wolf, Thomas G. Martin, Sandy W. Wong, Christopher Wong, Swetha Kambhampati, Vanessa E Kennedy, Chiung Yu Huang, and Nina Shah
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medicine.medical_specialty ,Receptors, Chimeric Antigen ,business.industry ,Macrophage Activation Syndrome ,T-Lymphocytes ,Hazard ratio ,Hematology ,medicine.disease ,chemistry.chemical_compound ,Cytokine release syndrome ,Exact test ,Tocilizumab ,chemistry ,Macrophage activation syndrome ,Internal medicine ,medicine ,Humans ,B-Cell Maturation Antigen ,Risk factor ,Multiple Myeloma ,business ,Multiple myeloma ,Febrile neutropenia - Abstract
Introduction Chimeric antigen receptor (CAR) T-cells can induce a rapid disease response but are frequently associated with immunologic toxicities. In addition to cytokine release syndrome (CRS), macrophage activation syndrome-like manifestations (MAS-L), characterized by uncontrolled immune activation, have been described (Shah et al, 2020). Traditional MAS definitions are challenging to apply in patients receiving CAR T cells, due to overlapping signs and symptoms with lymphodepletion and CRS. Therefore, we sought to develop novel criteria to characterize MAS-L following CAR T cells and used these criteria to identify risk factors for developing MAS-L. Methods We conducted a retrospective review of 55 patients who received B cell maturation antigen-directed CAR T cells for multiple myeloma from 11/1/17 - 5/1/20. Based on the labs readily available in our patient population, we defined MAS-L using the following criteria: 1) rate of ferritin rise ³ 100 mg/L/hour within a 24 hour period and 2) minimum fibrinogen 2 times the upper limit of normal. In developing these simplified criteria, we considered multiple laboratory markers of inflammation (ferritin, LDH, soluble interleukin receptor-2, natural killer cell activity) and end organ damage. Infection was defined as any culture positivity, febrile neutropenia, or clinical suspicion such that a new antimicrobial was started in the 30 days prior to CAR T cells. Wilcoxon rank-sums and Fisher’s exact test were used to compare continuous and categorical variables, respectively. Overall (OS) and progression-free survival (PFS) were compared using log-rank tests. Results Of the 55 patients, 12 (21.8%) met the above criteria for MAS-L with similar disease trajectories. Following CAR T cells, all 12 patients first developed CRS, characterized by an elevated C-reactive protein (CRP) and administration of tocilizumab, and subsequently developed MAS-L, characterized by decrease in fibrinogen and rapid rise of ferritin and LDH (Figure 1). Compared to the 45 patients who did not develop MAS-L, patients with MAS-L had similar baseline patient and disease characteristics (Table 1); however, a significantly higher proportion of patients with MAS-L had an infection prior to receiving CAR T cells (75% vs 9.3%, p Compared to patients who did not develop MAS-L, a similar proportion of MAS-L patients developed any CRS (100% vs 84%, p = 0.33) and ³ grade 2 CRS (50% vs 50%, p = 1). Neurotoxicity was more common in patients with MAS-L (42% vs 14%, p = 0.05). A greater proportion of patients with MAS-L received tocilizumab (100% vs 70%, p = 0.05), systemic steroids (92% vs 27%, p Following CAR T cell therapy, patients with MAS-L had longer hospitalizations (21 vs 19 days, p = 0.009) and a greater proportion required ICU-level care (27% vs 2%, p = 0.02). OS and PFS between the two groups were similar (p = 0.15 and 0.63, respectively), with a 1-year OS of 65.2% vs 90.6% and PFS of 35.4% vs 54.7% for patients with vs without MAS-L, respectively. In univariate logistic regression of baseline patient factors, disease characteristics, and ferritin, CRP, and D-dimer prior to receiving CAR T cells, only a history of documented infection in the 30 days prior to CAR T cells predicted MAS-L development (Hazard Ratio 29.2, 95% CI 5.54 - 154, p Conclusions In this analysis, we developed novel criteria for defining MAS-L following CAR T cell therapy and used these criteria to define the unique laboratory profile and clinical trajectory of patients with MAS-L. We also identify pre-existing infection as a strong risk factor for MAS-L development. Although patients with MAS-L frequently require prolonged monitoring, this immunologic toxicity can be mitigated with steroids, anakinra, and supportive care, and patients ultimately have similar survival compared to patients without MAS-L. Larger studies are needed to prospectively validate these novel criteria. Download : Download high-res image (447KB) Download : Download full-size image Disclosures Wolf: Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martin: Sanofi, Amgen, Seattle Genetics, JNJ - Janssen: Research Funding; Legend Biotech: Consultancy. Shah: BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Wong: Bristol Myers Squibb: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Janssen: Research Funding; Roche: Research Funding; Fortis: Research Funding; GSK: Research Funding.
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- 2021
12. The Prevalence of Uterine Fibroids in African American Women with Hemoglobin SS Sickle Cell Disease as Determined by Pelvic Magnetic Resonance Imaging
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Jessica Prescott, James Ronald, David C. Jones, Waleska M. Pabon-Ramos, and Jonathan G. Martin
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Adult ,Hemoglobin SS ,medicine.medical_specialty ,Uterine fibroids ,Hemoglobin, Sickle ,Anemia, Sickle Cell ,Disease ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Prevalence ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Retrospective Studies ,African american ,Pelvic MRI ,Leiomyoma ,medicine.diagnostic_test ,Obstetrics ,business.industry ,Magnetic resonance imaging ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,female genital diseases and pregnancy complications ,Black or African American ,Treatment Outcome ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Propensity score matching ,Female ,business - Abstract
This study explores the relationship between the development of uterine fibroids and hemoglobin SS sickle cell disease (SCD) by examining the prevalence of uterine fibroids as detected by pelvic magnetic resonance imaging (MRI) in African American (AA) women with and without SCD.A single-center, retrospective review was performed of all adult AA women at a large, academic medical center who received pelvic MRI from January 1, 2007 to December 31, 2018. Propensity score matching conditional on age and ZIP code evaluated the differences in fibroid prevalence between the two groups. Subanalyses by age in 10-year intervals were also performed.Twenty-one (23.9%) of 88 patients with SCD had fibroids on pelvic MRI versus 1493 (52.1%) of 2868 patients without SCD (p value0.001). After propensity score matching, 21 (24.7%) of 85 patients with SCD compared to 52 (61.2%) of 85 patients without SCD had fibroids (p value0.001). Subanalyses in 10-year age intervals showed significance for patients between 30 and 39 years old in which 4 (13.8%) of 29 SCD patients versus 374 (65.3%) of 573 no SCD patients had fibroids (p value0.001), and for patients between 40 and 49 years old in which 9 (42.9%) of 21 SCD patients versus 667 (73.8%) of 904 no SCD patients had fibroids (p value = 0.002).These findings indicate an overall significantly lower prevalence of uterine fibroids in AA women with SCD, suggesting that SCD may be protective against the development of uterine fibroids in these patients.
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- 2021
13. Posts in Primary Teeth–Past to Present: A Review of Literature
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Selvabalaji Arumugam, Prathima Gajula Shivashakarappa, Nandakumar Sundaramurthy, and Adeline G Martin
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Glass fiber post ,medicine.medical_specialty ,Primary (chemistry) ,business.industry ,Orthodontics ,Review Article ,Primary teeth ,stomatognathic diseases ,Dentin post ,Post ,stomatognathic system ,Family medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Metal post ,Periodontics ,Oral Surgery ,business - Abstract
Early childhood caries is indeed a devastative situation for both patients’ parents and pediatric dentists. The primary goal in treating severe early childhood caries is to restore normal function such as maintenance of mesiodistal and vertical dimension, prevention of alteration of mastication, phonetics (due to premature loss), development of parafunctional habits, and prevention of psychological problems affecting the self-esteem of a child. The restoration of primary dentition with extensive carious lesions is a complex clinical challenge of several dimensions. The severity of this condition in maxillary anterior teeth has prompted the extraction of teeth due to inadequate esthetic treatment options. The only concern with the severely destructed primary incisors is a lack of crown structure, which fails to support and adhere to a composite crown. Clinicians have preferred many restorative modalities for esthetic rehabilitation of badly decayed anterior primary teeth with numerous root canal retentive post and core systems with appropriate techniques to preserve those teeth until they are replaced by permanent teeth. This review highlights the various posts, their indications, principles, ideal properties, and the current concepts on their use in pediatric dentistry. How to cite this article Martin AG, Shivashakarappa PG, Arumugam S, et al. Posts in Primary Teeth–Past to Present: A Review of Literature. Int J Clin Pediatr Dent 2021;14(5):705–710.
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- 2021
14. Outcomes and Their State-level Variation in Patients Undergoing Surgery With Perioperative SARS-CoV-2 Infection in the USA
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Osaid, Alser, Ander Dorken Gallastegi, Anthony, Gebran, Kerry, Breen, Mohamad El Moheb, Apostolos, Gaitanidis, Leon, Naar, Brittany, Bankhead-Kendall, Hassan, Mashbari, Robert, D Sinyard, Lydia, R Maurer, Charu, Paranjape, George, C Velmahos, Dmitri, Nepogodiev, Aneel, Bhangu, Haytham M, A Kaafarani, Kwabena, Siaw-Acheampong, Leah, Argus, Daoud, Chaudhry, Brett, E Dawson, James, C Glasbey, Rohan, R Gujjuri, Conor, S Jones, Sivesh, K Kamarajah, Chetan, Khatri, James, M Keatley, Samuel, Lawday, Elizabeth, Li, Harvinder, Mann, Ella, J Marson, Kenneth, A Mclean, Maria, Picciochi, Elliott, H Taylor, Abhinav, Tiwari, Joana F, F Simoes, Isobel, M Trout, Mary, L Venn, Richard J, W Wilkin, Irida, Dajti, Arben, Gjata, Oussama, Kacimi, Luis, Boccalatte, Maria Marta Modolo, Daniel, Cox, Peter, Pockney, Philip, Townend, Felix, Aigner, Irmgard, Kronberger, Ahmed, Elgun, Amer, Alderazi, Kamral, Hossain, Greg, Padmore, Gabrielle, Vanramshorst, Ismail, Lawani, Duane, Wedderburn, Sonam, Dargay, Israël, Feraudy, Cerovac, Anis, Samir, Delibegovic, Alemayehu Ginbo Bedada, Gustavo, Ataide, Glauco, Baiocchi, Igor, Buarque, Muhammad, Gohar, Mihail, Slavchev, Jean Marie Vianney Butoyi, Chukwuemeka, Nwegbu, Arnav, Agarwal, Amanpreet, Brar, Janet, Martin, Maricarmen, Olivos, Dong-Lin, Ren, Wenhui, Lou, Jose, Calvache, Carlos Jose Perez Rivera, Ana Danic Hadzibegovic, Tomislav, Kopjar, Jakov, Mihanovic, Pablo, Avilés, Nikolaos, Gouvas, Jaroslav, Klat, René, Novysedlak, Nicolas, Amisi, Peter, Christensen, Alaa, El-Hussuna, Sylvia, Batista, Eddy, Lincango, Sameh, H Emile, Danilo Alfonso Arévalo Sandoval, Mengistu Gebreyohanes Mengesha, Samuel, Hailu, Hailu, Tamiru, Joonas, Kauppila, Johanna, Laukkarinen, Alexis, Arnaud, Roumanatou Bankole Sapin, Kebba, Marenah, Zaza, Demetrashvili, Andreas, A Schnitzbauer, Magdalena, Gruendl, Markus, Albertsmeiers, Hans, Lederhuber, Markus, Loffler, Bernard Ofori Appiah, Daniel, Acquah, Stephen, Tabiri, Symeon, Metallidis, Georgios, Tsoulfas, Maria Aguilera Lorena, Gustavo, Grecinos, Tamas, Mersich, Daniel, Wettstein, Atul, Suroy, Dhruv, Ghosh, Pranay, Pawar, Gabriele, Kembuan, Peiman, Brouk, Mohammad, Khosravi, Masoud, Mozafari, Ahmed, Adil, Helen, M Mohan, Oded, Zmora, Marco, Fiore, Gallo, G, Pata, Francesco, Gianluca, Pellino, Naoto, Kuroda, Sohei, Satoi, Yuki, Fujimoto, Faris, Ayasra, Mohammad, Chaar, Ildar, R Fakhradiyev, Intisar, Hisham, Jin-Young, Jang, Enver, Fekaj, Mohammad, Jamal, Anvar, Beisembaev, Muhammed, Elhadi, Aiste, Gulla, Luc, Samison, Jupsi, Neny, Palesa, Chisala, April, Roslani, Iran Irani Duran Sanchez, Laura Martinez Perez Maldonado, Antonio Ramos De La Medina, Jade, Nunez, Oumaima, Outani, Abd'Rashid, Nashidengo, Ashish Lal Shrestha, Rakesh, Shah, Pascal, Jonker, Schelto, Kruijff, Milou, Noltes, Pieter, Steinkamp, Willemijn van der Plas, Chris, Varghese, Deborah, Wright, Jorge, Neira, Adesoji, Ademuyiwa, Babatunde, Osinaike, Justina, Seyi-Olajide, Emmanuel, Williams, Sofija, Pejkova, Knut Magne Augestad, Kjetil, Soreide, Zainab Al Balushi, Ahmad, Qureshi, Raza, Sayyed, Mustafa Abu Mohsen Daraghmeh, Sadi, Abukhalaf, Moises, Cukier, Chris, Munguas, Hugo, Gomez, Sebastian, Shu, Ximena, Vasquez, Marie Dione Parreno-Sacdalan, Piotr, Major, José, Azevedo, Miguel, Cunha, Irene, Santos, Ahmad, Zarour, Eduard-Alexandru, Bonci, Ionut, Negoi, Sergey, Efetov, Andrey, Litvin, Faustin, Ntirenganya, Ehab, Alameer, Abdourahmane, Ndong, Dejan, Radenkovic, Ibrahim, Sesay, Frederick Koh Hong Xiang, Chew Min Hoe, James Ngu Chi Yong, Arpad, Panyko, Jurij, Kosir, Uros, Bele, Hassan, Ali, Rachel, Moore, Ncamsile, Nhlabathi, Ruth Blanco Colino, Ana Minaya Bravo, Umesh, Jayarajah, Dakshitha, Wickramasinghe, Mohammed, Elmujtaba, William, Jebril, Martin, Rutegård, Malin, Sund, Eleftherios, Gialamas, Karoline, Horisberger, Michel, Adamina, Muhammad, Alshaar, Abel, Huang, Ben, Mbwele, Varut, Lohsiriwat, Shane, Charles, Haithem, Jlassi, Arda, Isik, Sezai, Leventoğlu, Lekuya, Herve, Lekuya, Monka, Herman, Lule, Tom E, F Abbott, Ruth, Benson, Caruna, Ed, Sohini, Chakrabortee, Andreas, Demetriades, Anant, Desai, Thomas, D Drake, John, G Edwards, Jonathan, P Evans, Samuel, Ford, Christina, Fotopoulou, Ewen, Griffiths, Peter, Hutchinson, Michael, D Jenkinson, Tabassum, Khan, Stephen, Knight, Angelos, Kolias, Elaine, Leung, Siobhan, Mckay, Lisa, Norman, Riinu, Ots, Vidya, Raghavan, Keith, Roberts, Andrew, Schache, Richard, Shaw, Katie, Shaw, Neil, Smart, Grant, Stewart, Sudha, Sundar, Dale, Vimalchandran, Naomi, Wright, Slava, Kopetskiy, Sattar, Alshryda, Ian, Ganly, Haytham, Kaafarani, Brittany, Kendall, Fernando, Bonilla, Hamza Al Naggar, Mayaba, Maimbo, Dennis, Mazingi, J Wong, J, Napolitano, L, Hemmila, M, Amin, D, Abramowicz, S, M Roser, S, A Olson, K, Riley, C, Heron, C, Cardenas, T, Leede, E, Thornhill, M, B Haynes, A, Mcelhinney, K, Roward, S, D Trust, M, E Hill, C, G Teixeira, P, Etchill, E, Stevens, K, R Ladd, M, Long, C, Rose, J, Kent, A, Yesantharao, P, Vervoort, D, Jenny, H, Gabre-Kidan, A, Margalit, A, Tsai, L, Malapati, H, Yesantharao, L, Abdou, H, Diaz, J, Richmond, M, Clark, J, O'Meara, L, Hanna, N, Ying, Y, Fleming, J, Ovaitt, A, Gigliotti, J, Fuson, A, Cooper, Z, Salim, A, A Hirji, S, Brown, A, Chung, C, Hansen, L, U Okafor, B, Roxo, V, P Raut, C, S Jolissaint, J, A Mahvi, D, Kaafarani, H, Breen, K, Bankhead-Kendall, B, Alser, O, Mashbari, H, Velmahos, G, R Maurer, L, M El Moheb, Gaitanidis, A, Naar, L, A Christensen, M, Kapoen, C, Langeveld, K, M El Hechi, Mokhtari, A, H Haqqani, M, T Drake, F, Goldenberg-Sandau, A, Galbreath, B, Reinke, C, Ross, S, Thompson, K, Manning, D, Perkins, R, Eriksson, E, Evans, H, Masrur, M, Giulianotti, P, Benedetti, E, Chang, G, Ourieff, J, Dehart, D, Dorafshar, A, Price, T, R Bhama, A, Torquati, A, Cherullo, E, Kennedy, R, Myers, J, Rubin, K, S Ban, V, G Aoun, S, H Batjer, H, Caruso, J, Carmichael, H, G Velopulos, C, L Wright, F, Urban, S, C McIntyre Jr, R, J Schroeppel, T, A Hennessy, E, Dunn, J, Zier, L, Burlew, C, Coleman, J, P Colling, K, Hall, B, E Rice, H, S Hwang, E, A Olson, S, Moris, D, Verma, R, Hassan, R, Volpe, A, Merola, S, A O'Banion, L, Lilienstein, J, Dirks, R, Marwan, H, Almasri, M, Kulkarni, G, Mehdi, M, Abouassi, A, Abdallah, M, M San Andrés, Eid, J, Aigbivbalu, E, Sundaresan, J, George, B, Ssentongo, A, Ssentongo, P, S Oh, J, Hazelton, J, Maines, J, Gusani, N, Garner, M, Horvath, S, Zheng, F, Ujiki, M, Kinnaman, G, Meagher, A, Sharma, I, Holler, E, Mckenzie, K, Chan, J, Fretwell, K, W Nugent 3rd, Khalil, A, Chen, D, Post, N, Rostkowski, T, Brahmbhatt, D, Huynh, K, L Hibbard, M, Schellenberg, M, R C, G Martin, Bhutiani, N, Giorgakis, E, Laryea, J, Bhavaraju, A, Sexton, K, Roberts, M, Kost, M, Kimbrough, M, Burdine, L, Kalkwarf, K, Robertson, R, Gosain, A, Camp, L, Lewit, R, P Kronenfeld, J, Urrechaga, E, Goel, N, Rattan, R, Hart, V, Allen, M, Gilna, G, Cioci, A, Ruiz, G, Rakoczy, K, Pavlis, W, Saberi, R, Morris, R, S Karam, B, C E, M Brathwaite, Liu, H, Petrone, P, Hakmi, H, H Sohail, A, Baltazar, G, Heckburn, R, M Nygaard, R, T Colonna, E, W Endorf, F, J Hill, M, Maiga, A, Dennis, B, H Levin, J, Lallemand, M, Choron, R, Peck, G, Soliman, F, Rehman, S, Glass, N, Juthani, B, Deisher, D, M Ruzgar, N, J Ullrich, S, Sion, M, Paranjape, C, R Kar, A, Gillezeau, C, Rapp, J, Taioli, E, A Miles, B, Alpert, N, Podolsky, D, L Coleman, N, P Callahan, M, Ganly, I, Brown, L, J R, T Monson, Dehal, A, Abbas, A, Soliman, A, Kim, B, Jones, C, D Dauer, M, Renza-Stingone, E, Hernandez, E, Gokcen, E, Kropf, E, Sufrin, H, Hirsch, H, Ross, H, Engel, J, Sewards, J, Poggio, J, Sanserino, K, Rae, L, Philp, M, Metro, M, Mcnelis, P, Petrov, R, Pazionis, T, Till, B, Lamm, R, J Rios-Diaz, A, Palazzo, F, Rosengart, M, Nicholson, K, M Carrick, M, Rodkey, K, Suri, A, Callcut, R, Nicholson, S, Talathoti, N, Klaristenfeld, D, Biffl, W, Marsh, C, Schaffer, K, E Berndtson, A, Averbach, S, Curry, T, Kwan-Feinberg, R, Consorti, E, Gonzalez, R, Grolman, R, Liu, T, Merzlikin, O, K Abel, M, Ozgediz, D, Boeck, M, Z Kornblith, L, Nunez-Garcia, B, Robinson, B, Park, P, F Utria, A, E Rice-Townsend, S, Javid, P, Hauptman, J, Kieran, K, Nehra, D, Walters, A, Cuschieri, J, H Davidson, G, Nunez, J, Cosker, R, Eckhouse, S, Choudhry, A, Marx, W, Jamil, T, Seegert, S, Al-Embideen, S, Quintana, M, Jackson, H, D Wexner, S, Kent, I, N Martins, P, Xiao, Liu, and Alistair, Denniston
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Male ,medicine.medical_specialty ,Revised Cardiac Risk Index ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,pulmonary complications ,Malignancy ,Time-to-Treatment ,Postoperative Complications ,Sex Factors ,Risk Factors ,medicine ,COVID-19, COVIDSurg, elective surgery, emergency surgery, mortality, pulmonary complications ,Humans ,In patient ,Prospective Studies ,emergency surgery ,Elective surgery ,Aged ,Respiratory Distress Syndrome ,SARS-CoV-2 ,business.industry ,Pulmonary Complication ,Age Factors ,COVID-19 ,Pneumonia ,Perioperative ,Middle Aged ,COVIDSurg ,elective surgery ,mortality ,medicine.disease ,United States ,Surgery ,Multicenter study ,Elective Surgical Procedures ,Female ,business - Abstract
Objective To report the 30-day outcomes of patients with perioperative SARS-CoV-2 infection undergoing surgery in the USA. Summary background data Uncertainty regarding the postoperative risks of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists. Methods As part of the COVIDSurg multicenter study, all patients aged ≥17 years undergoing surgery between January 1 and June 30, 2020 with perioperative SARS-CoV-2 infection in 70 hospitals across 27 states were included. The primary outcomes were 30-day mortality and pulmonary complications. Multivariable analyses (adjusting for demographics, comorbidities, and procedure characteristics) were performed to identify predictors of mortality. Results A total of 1,581 patients were included; more than half of them were males (n= 822, 52.0%) and older than 50 years (n=835, 52.8%). Most procedures (n=1,261, 79.8%) were emergent, and laparotomies (n= 538, 34.1%). The mortality and pulmonary complication rates were 11.0 and 39.5%, respectively. Independent predictors of mortality included age ≥70 years (OR 2.46, 95% CI [1.65-3.69]), male sex (2.26 [1.53-3.35]), ASA grades 3-5 (3.08 [1.60-5.95]), emergent surgery (2.44 [1.31-4.54]), malignancy (2.97 [1.58-5.57]), respiratory comorbidities (2.08 [1.30-3.32]), and higher Revised Cardiac Risk Index (1.20 [1.02-1.41]). While statewide elective cancelation orders were not associated with a lower mortality, a sub-analysis showed it to be associated with lower mortality in those who underwent elective surgery (0.14 [0.03-0.61]). Conclusions Patients with perioperative SARS-CoV-2 infection have a significantly high risk for postoperative complications, especially elderly males. Postponing elective surgery and adopting non-operative management, when reasonable, should be considered in the USA during the pandemic peaks.
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- 2021
15. Educational attainment of same-sex and opposite-sex dizygotic twins
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Glen E. Duncan, Juan R. Ordoñana, Aline Jelenkovic, Esther Rebato, Amie E. Hwang, Wendy Cozen, Zengchang Pang, Weilong Li, Matthew Hotopf, Sisira Siribaddana, Leonie Helen Bogl, Dedra Buchwald, Robert F. Krueger, Brooke M. Huibregtse, Dorret I. Boomsma, Karri Silventoinen, Catherine Derom, Meike Bartels, Lucía Colodro-Conde, Ruth J. F. Loos, Catharina E. M. van Beijsterveldt, Athula Sumathipala, Jessica Tyler, Sarah E. Medland, Nicholas G. Martin, Fruhling Rijsdijk, Robert Vlietinck, Shandell Pahlen, Tracy L. Nelson, Kauko Heikkilä, Richard J. Rose, Anna K. Dahl Aslan, Thorkild I. A. Sørensen, Virgilia Toccaceli, Patrik K. E. Magnusson, Judy L. Silberg, John L. Hopper, Thomas M. Mack, Emanuela Medda, Grant W. Montgomery, Antti Latvala, Juan F. Sánchez-Romera, Qihua Tan, Dongfeng Zhang, Gonneke Willemsen, Matt McGue, Nancy L. Pedersen, Keith E. Whitfield, Jaakko Kaprio, Eero Vuoksimaa, Lorenza Nisticò, Christian Kandler, Hermine H. Maes, Robin P. Corley, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Personalized Medicine, APH - Methodology, Helsinki Inequality Initiative (INEQ), Demography, Population Research Unit (PRU), Center for Population, Health and Society, Sociology, Department of Social Research (2010-2017), Institute for Molecular Medicine Finland, Clinicum, Department of Physiology, Department of Public Health, Cognitive and Brain Aging, Faculty Common Matters (Faculty of Medicine), Institute of Criminology and Legal Policy, Faculty Common Matters (Faculty of Education), and Technology Centre
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Male ,Twins ,Dizygotic twins ,Education ,Cohort Studies ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Endocrinology ,5. Gender equality ,Sex differences in education ,RA0421 ,Twins, Dizygotic ,Humans ,Medicine ,Testosterone ,10. No inequality ,Birth Year ,Medicinsk genetik ,030304 developmental biology ,Sex Characteristics ,0303 health sciences ,Psykologi (exklusive tillämpad psykologi) ,Endocrine and Autonomic Systems ,business.industry ,Public Health, Global Health, Social Medicine and Epidemiology ,Testosterone (patch) ,Twin study ,Testosterone exposure ,Confidence interval ,Educational attainment ,Psychology (excluding Applied Psychology) ,Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi ,5141 Sociology ,Cohort ,Educational Status ,1182 Biochemistry, cell and molecular biology ,Female ,business ,Medical Genetics ,RA ,Twin testosterone transfer hypothesis ,SDG 4 - Quality Education ,030217 neurology & neurosurgery ,Demography - Abstract
Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (β = −0.05 educational years, 95% CI −0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (β = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers. CC BY 4.0Correspondence Address: Silventoinen, K.; University of Helsinki, P.O. Box 18, Finland; email: karri.silventoinen@helsinki.fi© 2021 The Authors
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- 2021
16. Approaches to investigate crop responses to ozone pollution: from O 3 ‐FACE to satellite‐enabled modeling
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Duncan G. Martin, Hannah J. Demler, Christopher M. Montes, Elizabeth A. Ainsworth, and Shuai Li
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Pollutant ,Pollution ,Free-air concentration enrichment ,Crop yield ,media_common.quotation_subject ,fungi ,Air pollution ,food and beverages ,Climate change ,Cell Biology ,Plant Science ,Biology ,medicine.disease_cause ,Crop ,Environmental protection ,Genetics ,medicine ,Productivity ,media_common - Abstract
Ozone (O3 ) is a damaging air pollutant to crops. As one of the most reactive oxidants known, O3 rapidly forms other reactive oxygen species (ROS) once it enters leaves through stomata. Those ROS in turn can cause oxidative stress, reduce photosynthesis, accelerate senescence, and decrease crop yield. To improve and adapt our feed, fuel, and food supply to rising O3 pollution, a number of Free Air Concentration Enrichment (O3 -FACE) facilities have been developed around the world and have studied key staple crops. In this review, we provide an overview of the FACE facilities and highlight some of the lessons learned from the last two decades of research. We discuss the differences between C3 and C4 crop responses to elevated O3 , the possible trade-off between productivity and protection, genetic variation in O3 response within and across species, and how we might leverage this observed variation for crop improvement. We also highlight the need to improve understanding of the interaction between rising O3 pollution and other aspects of climate change, notably drought. Finally, we propose the use of globally modeled O3 data that are available at increasing spatial and temporal resolutions to expand upon the research conducted at the limited number of global O3 -FACE facilities.
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- 2021
17. Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11
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Thomas A. Ravenscroft, Jennifer B. Phillips, Elizabeth Fieg, Sameer S. Bajikar, Judy Peirce, Jeremy Wegner, Alia A. Luna, Eric J. Fox, Yi-Lin Yan, Jill A. Rosenfeld, Jonathan Zirin, Oguz Kanca, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanya, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo Moretti, Paolo M. Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina GS. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Vandana Shashi, Jimann Shin, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Paul J. Benke, Eric S. Cameron, Vincent Strehlow, Konrad Platzer, Rami Abou Jamra, Chiara Klöckner, Matthew Osmond, Thomas Licata, Samantha Rojas, David Dyment, Josephine S.C. Chong, Sharyn Lincoln, John H. Postlethwait, Joel Krier, and Hugo J. Bellen
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0301 basic medicine ,Craniofacial abnormality ,Mutation, Missense ,030105 genetics & heredity ,Biology ,Article ,Frameshift mutation ,Craniofacial Abnormalities ,03 medical and health sciences ,medicine ,Animals ,Humans ,Missense mutation ,Craniofacial ,Allele ,Zebrafish ,Genetics (clinical) ,Loss function ,Genetics ,medicine.disease ,biology.organism_classification ,Phenotype ,Spine ,Growth Differentiation Factors ,030104 developmental biology ,Bone Morphogenetic Proteins - Abstract
Purpose Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. Methods We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. Results Patients with variants in GDF11 presented with craniofacial (5/6) , vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6) and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) alleles whereas the missense variants in our cohort are partial LOF variants. Conclusion GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.
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- 2021
18. Proton pump inhibitor use is associated with increased rates of post-TIPS hepatic encephalopathy: Replication in an independent patient cohort
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Andrew J. Muir, Charles Y. Kim, Paul V. Suhocki, Nicholas T. Befera, Waleska M. Pabon-Ramos, Rui Dai, Alan A. Sag, Jonathan G. Martin, James Ronald, and Tony P. Smith
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Liver Cirrhosis ,Male ,medicine.medical_specialty ,medicine.drug_class ,Proton-pump inhibitor ,Rate ratio ,Gastroenterology ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Poisson regression ,Hepatic encephalopathy ,Survival analysis ,Retrospective Studies ,business.industry ,Hazard ratio ,Proton Pump Inhibitors ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Hepatic Encephalopathy ,030220 oncology & carcinogenesis ,Cohort ,symbols ,Portasystemic Shunt, Transjugular Intrahepatic ,business - Abstract
Purpose Proton pump inhibitor (PPI) use is a potential risk factor for hepatic encephalopathy (HE), but few studies have examined the effect on post-TIPS HE. The purpose of this study was to determine whether PPIs are associated with increased rates of post-TIPS HE in an independent patient cohort. Materials and methods This single-institution retrospective study analyzed 86 patients (54 male, mean age 58.2) following TIPS from 1/1/2017 to 12/31/2019. Dates of PPI usage and episodes of new or worsening HE were recorded. Poisson regression with generalized estimating equations was used to test for association between PPI use and post-TIPS HE and to test for dose dependence. Post-TIPS HE was also analyzed using the Andersen-Gill survival model for recurrent events. Results There were 1.88 episodes of new or worsening post-TIPS HE per person-year among 35 patients on uninterrupted PPIs therapy, 1.95 on PPIs and 0.94 off PPIs among 35 patients on intermittent therapy, and 0.47 among 16 patients never on PPIs. PPI use was significantly associated with post-TIPS HE in both univariable (incidence rate ratio (IRR) = 2.62; CI = 1.41–4.84; p = 0.002) and multivariable (IRR = 2.31; CI = 1.37–3.89; p = 0.002) regression. Analysis of only those patients on PPIs showed increased rates of HE with higher doses (IRR = 1.17 per 10 mg omeprazole equivalent; CI = 1.04–1.33; p = 0.011). Recurrent events survival analysis supported the association between PPI use and HE in univariable (hazard ratio (HR) = 2.17; CI = 1.19–3.95; p = 0.011) and multivariable (HR = 1.87; CI = 1.12–3.13; p = 0.017) analysis. Conclusion In an independent patient cohort PPI use was associated with increased rates of new or worsening post-TIPS HE.
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- 2021
19. Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain
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Felix Marbach, Georgi Stoyanov, Florian Erger, Constantine A. Stratakis, Nikolaos Settas, Edra London, Jill A. Rosenfeld, Erin Torti, Chad Haldeman-Englert, Evgenia Sklirou, Elena Kessler, Sophia Ceulemans, Stanley F. Nelson, Julian A. Martinez-Agosto, Christina G.S. Palmer, Rebecca H. Signer, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennett, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Daya, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Joel B. Krier, Grace L. LaMoure, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Calum A. MacRae, Ellen F. Macnamara, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Paolo Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Deepak A. Rao, Wendy Raskind, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, C. Ron Scott, Daryl A. Scott, Vandana Shashi, Jimann Shin, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, null Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Marisa V. Andrews, Dorothy K. Grange, Rebecca Willaert, Richard Person, Aida Telegrafi, Aaron Sievers, Magdalena Laugsch, Susanne Theiß, YuZhu Cheng, Olivier Lichtarge, Panagiotis Katsonis, Amber Stocco, and Christian P. Schaaf
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0301 basic medicine ,Apraxias ,Autism Spectrum Disorder ,Pain ,Biology ,Apraxia ,Article ,03 medical and health sciences ,0302 clinical medicine ,Neurodevelopmental disorder ,Pregnancy ,Intellectual Disability ,Intellectual disability ,medicine ,Humans ,Missense mutation ,Global developmental delay ,Genetics (clinical) ,Genetics ,medicine.disease ,Phenotype ,Human genetics ,030104 developmental biology ,Neurodevelopmental Disorders ,Autism spectrum disorder ,Cyclic AMP-Dependent Protein Kinase RIbeta Subunit ,Female ,030217 neurology & neurosurgery - Abstract
Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
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- 2021
20. BAG3 expression and sarcomere localization in the human heart are linked to HSF-1 and are differentially affected by sex and disease
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Toni R. Pak, Christine S. Moravec, Sara Tawfik, Thomas G Martin, and Jonathan A. Kirk
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Adult ,Cardiomyopathy, Dilated ,Male ,Sarcomeres ,0301 basic medicine ,endocrine system ,medicine.medical_specialty ,Myofilament ,Physiology ,medicine.drug_class ,Heart Ventricles ,Ovariectomy ,Cardiomyopathy ,Gene Expression ,030204 cardiovascular system & hematology ,Biology ,BAG3 ,Sarcomere ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Heat Shock Transcription Factors ,Myofibrils ,Physiology (medical) ,Internal medicine ,Gene expression ,medicine ,Animals ,Humans ,Myocytes, Cardiac ,Adaptor Proteins, Signal Transducing ,Aged ,Myocardium ,Dilated cardiomyopathy ,Middle Aged ,medicine.disease ,Rats ,030104 developmental biology ,Endocrinology ,Microscopy, Fluorescence ,Estrogen ,Heart failure ,cardiovascular system ,Female ,Apoptosis Regulatory Proteins ,Cardiology and Cardiovascular Medicine ,Research Article - Abstract
Mutations to the sarcomere-localized cochaperone protein Bcl2-associated athanogene 3 (BAG3) are associated with dilated cardiomyopathy (DCM) and display greater penetrance in male patients. Decreased protein expression of BAG3 is also associated with nongenetic heart failure; however, the factors regulating cardiac BAG3 expression are unknown. Using left ventricular (LV) tissue from nonfailing and DCM human samples, we found that whole LV BAG3 expression was not significantly impacted by DCM or sex; however, myofilament localized BAG3 was significantly decreased in males with DCM. Females with DCM displayed no changes in BAG3 compared with nonfailing. This sex difference appears to be estrogen independent, as estrogen treatment in ovariectomized female rats had no impact on BAG3 expression. BAG3 gene expression in noncardiac cells is primarily regulated by the heat shock transcription factor-1 (HSF-1). We show whole LV HSF-1 expression and nuclear localized/active HSF-1 each displayed a striking positive correlation with whole LV BAG3 expression. We further found that HSF-1 localizes to the sarcomere Z-disc in cardiomyocytes and that this myofilament-associated HSF-1 pool decreases in heart failure. The decrease of HSF-1 was more pronounced in male patients and tightly correlated with myofilament BAG3 expression. Together our findings indicate that cardiac BAG3 expression and myofilament localization are differentially impacted by sex and disease and are linked to HSF-1. NEW & NOTEWORTHY Myofilament BAG3 expression decreases in male patients with nonischemic DCM but is preserved in female patients with DCM. BAG3 expression in the human heart is tightly linked to HSF-1 expression and nuclear translocation. HSF-1 localizes to the sarcomere Z-disc in the human heart. HSF-1 expression in the myofilament fraction decreases in male patients with DCM and positively correlates with myofilament BAG3.
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- 2021
21. Examining the Vanishing Twin Hypothesis of Neural Tube Defects
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Wendy P. Robinson, Dorret I. Boomsma, Nicholas G. Martin, Jenny van Dongen, Allan F. McRae, Veronika V. Odintsova, Scott D. Gordon, Judith G. Hall, APH - Personalized Medicine, APH - Mental Health, Biological Psychology, and APH - Methodology
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0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Placenta ,Biology ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,monozygotic twins ,SDG 3 - Good Health and Well-being ,Pregnancy ,Anencephaly ,medicine ,Diseases in Twins ,Twins, Dizygotic ,Humans ,Epigenetics ,Genetics (clinical) ,Neural tube defects ,Genetics ,Vanishing twin ,DNA methylation ,Spina bifida ,Twinning, Monozygotic ,Neural tube ,Obstetrics and Gynecology ,Methylation ,Twins, Monozygotic ,medicine.disease ,spina bifida ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Chorionic villi ,Female ,anencephaly ,epigenetic - Abstract
Strong associations between neural tube defects (NTDs) and monozygotic (MZ) twinning have long been noted, and it has been suggested that NTD cases who do not present as MZ twins may be the survivors of MZ twinning events. We have recently shown that MZ twins carry a strong, distinctive DNA methylation signature and have developed an algorithm based on genomewide DNA methylation array data that distinguishes MZ twins from dizygotic twins and other relatives at well above chance level. We have applied this algorithm to published methylation data from five fetal tissues (placental chorionic villi, kidney, spinal cord, brain and muscle) collected from spina bifida cases (n = 22), anencephalic cases (n = 15) and controls (n = 19). We see no difference in signature between cases and controls, providing no support for a common etiological role of MZ twinning in NTDs. The strong associations therefore continue to await elucidation.
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- 2021
22. Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases
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Shilpa Nadimpalli Kobren, Dustin Baldridge, Matt Velinder, Joel B. Krier, Kimberly LeBlanc, Cecilia Esteves, Barbara N. Pusey, Stephan Züchner, Elizabeth Blue, Hane Lee, Alden Huang, Lisa Bastarache, Anna Bican, Joy Cogan, Shruti Marwaha, Anna Alkelai, David R. Murdock, Pengfei Liu, Daniel J. Wegner, Alexander J. Paul, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennett, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Daya, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Grace L. LaMoure, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Brendan H. Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Calum A. MacRae, Ellen F. Macnamara, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martinez-Agosto, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Paolo Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stanley F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Aaron Quinlan, Archana N. Raja, Deepak A. Rao, Wendy Raskind, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, C. Ron Scott, Daryl A. Scott, Vandana Shashi, Jimann Shin, Rebecca H. Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, null Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, and Shamil R. Sunyaev
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Prioritization ,Genome ,medicine.diagnostic_test ,Genomic sequencing ,Multimodal data ,Computational Biology ,Structural variant ,Genomics ,Undiagnosed Diseases ,Data science ,Shruti ,Article ,Workflow ,Biomedical data ,medicine ,Humans ,Genetic Testing ,Psychology ,Software ,Genetics (clinical) ,Genetic testing - Abstract
Author(s): Kobren, Shilpa Nadimpalli; Baldridge, Dustin; Velinder, Matt; Krier, Joel B; LeBlanc, Kimberly; Esteves, Cecilia; Pusey, Barbara N; Zuchner, Stephan; Blue, Elizabeth; Lee, Hane; Huang, Alden; Bastarache, Lisa; Bican, Anna; Cogan, Joy; Marwaha, Shruti; Alkelai, Anna; Murdock, David R; Liu, Pengfei; Wegner, Daniel J; Paul, Alexander J; Undiagnosed Diseases Network; Sunyaev, Shamil R; Kohane, Isaac S | Abstract: PurposeGenomic sequencing has become an increasingly powerful and relevant tool to be leveraged for the discovery of genetic aberrations underlying rare, Mendelian conditions. Although the computational tools incorporated into diagnostic workflows for this task are continually evolving and improving, we nevertheless sought to investigate commonalities across sequencing processing workflows to reveal consensus and standard practice tools and highlight exploratory analyses where technical and theoretical method improvements would be most impactful.MethodsWe collected details regarding the computational approaches used by a genetic testing laboratory and 11 clinical research sites in the United States participating in the Undiagnosed Diseases Network via meetings with bioinformaticians, online survey forms, and analyses of internal protocols.ResultsWe found that tools for processing genomic sequencing data can be grouped into four distinct categories. Whereas well-established practices exist for initial variant calling and quality control steps, there is substantial divergence across sites in later stages for variant prioritization and multimodal data integration, demonstrating a diversity of approaches for solving the most mysterious undiagnosed cases.ConclusionThe largest differences across diagnostic workflows suggest that advances in structural variant detection, noncoding variant interpretation, and integration of additional biomedical data may be especially promising for solving chronically undiagnosed cases.
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- 2021
23. Genetic Susceptibility to Pneumonia: A GWAS Meta-Analysis Between the UK Biobank and FinnGen
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Gabriel Cuellar-Partida, Miguel E. Rentería, Karla X. Vazquez-Prada, Nicholas G. Martin, Luis M. García-Marín, Pik Kho, and Adrian I. Campos
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Genetics ,business.industry ,Australia ,Obstetrics and Gynecology ,Respiratory infection ,Genome-wide association study ,Pneumonia ,medicine.disease ,Genetic correlation ,United Kingdom ,Chromosome 15 ,Meta-analysis ,Pediatrics, Perinatology and Child Health ,Genetic variation ,medicine ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,business ,Genetics (clinical) ,Biological Specimen Banks ,Genome-Wide Association Study - Abstract
Pneumonia is a respiratory condition with complex etiology. Host genetic variation is thought to contribute to individual differences in susceptibility and symptom manifestation. Here, we analyze pneumonia data from the UK Biobank (14,780 cases and 439,096 controls) and FinnGen (9980 cases and 86,519 controls) and perform a genomewide association study meta-analysis. We use gene-based tests, colocalization, genetic correlation, latent causal variable (LCV) and polygenic prediction in an independent Australian sample (N = 5595) to draw insights into the etiology of pneumonia risk. We identify two independent loci on chromosome 15 (lead single-nucleotide polymorphisms rs2009746 and rs76474922) to be associated with pneumonia (p < 5e−8). Gene-based tests revealed 18 genes in chromosomes 15, 16 and 9, including IL127, PBX3, ApoB receptor (APOBR) and smoking related genes CHRNA3/5, statistically associated with pneumonia. We observed genetic correlations between pneumonia and cardiorespiratory, psychiatric and inflammatory related traits. LCV analysis suggests a strong genetic causal relationship with cardiovascular health phenotypes. Polygenic risk scores for pneumonia significantly predicted self-reported pneumonia in an independent sample, albeit with a small effect size (OR = 1.11 95% CI [1.04, 1.19], p
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- 2021
24. Phenome-wide screening of GWAS data reveals the complex causal architecture of obesity
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Pik Fang Kho, Luis M. García-Marín, Miguel E. Rentería, Gabriel Cuellar-Partida, Nicholas G. Martin, and Adrian I. Campos
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medicine.medical_specialty ,0303 health sciences ,business.industry ,Public health ,030305 genetics & heredity ,Loneliness ,Anthropometry ,Biology ,Phenome ,Irritability ,medicine.disease ,Phenotype ,Obesity ,Human genetics ,03 medical and health sciences ,Neurodevelopmental disorder ,Diabetes mellitus ,Genetics ,medicine ,medicine.symptom ,business ,Genetics (clinical) ,030304 developmental biology ,Clinical psychology ,Genetic association - Abstract
In the present study, we sought to identify causal relationships between obesity and other complex traits and conditions using a data-driven hypothesis-free approach that uses genetic data to infer causal associations. We leveraged available summary-based genetic data from genome-wide association studies on 1498 phenotypes and applied the latent causal variable method (LCV) between obesity and all traits. We identified 110 traits causally associated with obesity. Of those, 109 were causal outcomes of obesity, while only leg pain in calves was a causal determinant of obesity. Causal outcomes of obesity included 26 phenotypes associated with cardiovascular diseases, 22 anthropometric measurements, nine with the musculoskeletal system, nine with behavioural or lifestyle factors including loneliness or isolation, six with respiratory diseases, five with body bioelectric impedances, four with psychiatric phenotypes, four related to the nervous system, four with disabilities or long-standing illness, three with the gastrointestinal system, three with use of analgesics, two with metabolic diseases, one with inflammatory response and one with the neurodevelopmental disorder ADHD, among others. In particular, some causal outcomes of obesity included hypertension, stroke, ever having a period of extreme irritability, low forced vital capacity and forced expiratory volume, diseases of the musculoskeletal system, diabetes, carpal tunnel syndrome, loneliness or isolation, high leukocyte count, and ADHD. Our results indicate that obesity causally affects a wide range of traits and comorbid diseases, thus providing an overview of the metabolic, physiological, and neuropsychiatric impact of obesity on human health.
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- 2021
25. A phase 2 study of isatuximab monotherapy in patients with multiple myeloma who are refractory to daratumumab
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Ravi Vij, Dorothée Semiond, Aurore Perrot, Claire Brillac, Thomas G. Martin, Djordje Atanackovic, Kathryn P. Corzo, Jeffrey A. Zonder, Sandrine Macé, Cristina Gasparetto, Philippe Moreau, Ludek Pour, Joseph Mikhael, Cyrille Hulin, Qilong Weng, Karim Belhadj-Merzoug, Laure Vincent, Samira Bensfia, Nashat Gabrail, Xavier Leleu, and Ivan Spicka
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Isatuximab ,Oncology ,medicine.medical_specialty ,business.industry ,MEDLINE ,Phases of clinical research ,Daratumumab ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Hematology ,medicine.disease ,Text mining ,Refractory ,Internal medicine ,Medicine ,In patient ,business ,Multiple myeloma ,RC254-282 - Published
- 2021
26. In a multi-institutional cohort of myeloid sarcomas, NFE2 mutation prevalence is lower than previously reported
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Joel F. Gradowski, Richard D. Press, Pranil K. Chandra, Guang Fan, Anna B. Owczarczyk, Nathanael G. Bailey, Heather L. Mulder, Yiwei Liu, Tauangtham Anekpuritanang, John Easton, Michael G. Martin, Kohei Hagiwara, Matthew M. Klairmont, Jinghui Zhang, Philipp W. Raess, and Jennifer Dunlap
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Oncology ,medicine.medical_specialty ,Myeloid ,business.industry ,Hematology ,Cohort Studies ,medicine.anatomical_structure ,Internal medicine ,Mutation ,Mutation (genetic algorithm) ,Cohort ,Prevalence ,medicine ,Humans ,Sarcoma, Myeloid ,business - Published
- 2021
27. A Chilling Conclusion to the Hypothermia Debate?
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Robert J. Klemisch, Vasisht Srinivasan, and Emily G. Martin
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medicine.medical_specialty ,Annals ,business.industry ,Emergency medicine ,Emergency Medicine ,MEDLINE ,Medicine ,Hypothermia ,medicine.symptom ,business ,Journal club - Published
- 2021
28. Epidermal growth factor receptor-dependent maintenance of cardiac contractility
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Rhonda L. Carter, Erin McEachern, Joseph Y. Cheung, Jianliang Song, Ana Maria Lucchese, Erhe Gao, Douglas G. Tilley, Ama Dedo Okyere, Toby P. Thomas, Jonathan A. Kirk, Thomas G Martin, Viren C Patwa, Sudarsan Rajan, Joshua Strong, Melissa Landy, Shuchi Guo, and Walter J. Koch
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Cardiac function curve ,Physiology ,Contractility ,Mice ,Troponin T ,Downregulation and upregulation ,Physiology (medical) ,medicine ,Animals ,Myocytes, Cardiac ,Epidermal growth factor receptor ,Receptor ,biology ,business.industry ,Isoproterenol ,Original Articles ,Dependovirus ,medicine.disease ,Myocardial Contraction ,Phospholamban ,ErbB Receptors ,Heart failure ,Cancer research ,biology.protein ,Cardiology and Cardiovascular Medicine ,business ,Homeostasis - Abstract
Aims Epidermal growth factor receptor (EGFR) is essential to the development of multiple tissues and organs and is a target of cancer therapeutics. Due to the embryonic lethality of global EGFR deletion and conflicting reports of cardiac-overexpressed EGFR mutants, its specific impact on the adult heart, normally or in response to chronic stress, has not been established. Using complimentary genetic strategies to modulate cardiomyocyte-specific EGFR expression, we aim to define its role in the regulation of cardiac function and remodeling. Methods and results A floxed EGFR mouse model with α-myosin heavy chain-Cre-mediated cardiomyocyte-specific EGFR downregulation (CM-EGFR-KD mice) developed contractile dysfunction by 9 weeks of age, marked by impaired diastolic relaxation, as monitored via echocardiographic, hemodynamic and isolated cardiomyocyte contractility analyses. This contractile defect was maintained over time without overt cardiac remodeling until 10 months of age, after which the mice ultimately developed severe heart failure and reduced lifespan. Acute downregulation of EGFR in adult floxed EGFR mice with adeno-associated virus 9 (AAV9)-encoded Cre with a cardiac troponin T promoter (AAV9-cTnT-Cre) recapitulated the CM-EGFR-KD phenotype, while AAV9-cTnT-EGFR treatment of adult CM-EGFR-KD mice rescued the phenotype. Notably, chronic administration of the β-adrenergic receptor (βAR) agonist isoproterenol effectively and reversibly compensated for the contractile dysfunction in the absence of cardiomyocyte hypertrophy in CM-EGFR-KD mice. Mechanistically, EGFR downregulation reduced the expression of protein phosphatase 2 A (PP2A) regulatory subunit Ppp2r3a/PR72, which was associated with decreased phosphorylation of phospholamban (PLB) and Ca2+ clearance, and whose re-expression via AAV9-cTnT-PR72 rescued the CM-EGFR-KD phenotype. Conclusions Altogether our study highlights a previously unrecognized role for EGFR in maintaining contractile homeostasis under physiologic conditions in the adult heart via regulation of PR72 expression. Translational perspective Our study highlights a previously unrecognized role for EGFR in maintaining contractile homeostasis under physiologic conditions in the adult heart via regulation of PR72, a PP2A regulatory subunit with an unknown impact on cardiac function. Further, we have shown that cardiomyocyte-expressed EGFR is required for the promotion of cardiac hypertrophy under conditions of chronic catecholamine stress. Altogether, our study provides new insight into the dynamic nature of cardiomyocyte-specific EGFR.
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- 2021
29. Chemoproteomic Profiling of Covalent XPO1 Inhibitors to Assess Target Engagement and Selectivity
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K Guckian, S Couvertier, J A Ward, D S Johnson, L Zhang, J G Martin, Felix Feyertag, and Huber Kvm.
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Receptors, Cytoplasmic and Nuclear ,Antineoplastic Agents ,Karyopherins ,010402 general chemistry ,01 natural sciences ,Biochemistry ,XPO1 ,In vivo ,Cell Line, Tumor ,medicine ,Humans ,Solid tumor ,Molecular Biology ,010405 organic chemistry ,Mechanism (biology) ,Amyotrophic Lateral Sclerosis ,Organic Chemistry ,Target engagement ,Triazoles ,medicine.disease ,0104 chemical sciences ,Hydrazines ,Covalent bond ,Cancer research ,Molecular Medicine ,Glioblastoma ,Selectivity - Abstract
Selinexor, a covalent XPO1 inhibitor, is approved in the USA in combination with dexamethasone for penta-refractory multiple myeloma. Additional XPO1 covalent inhibitors are currently in clinical trials for multiple diseases including hematologic malignancies, solid tumor malignancies, glioblastoma multiforme (GBM), and amyotrophic lateral sclerosis (ALS). It is important to measure the target engagement and selectivity of covalent inhibitors to understand the degree of engagement needed for efficacy, while avoiding both mechanism-based and off-target toxicity. Herein, we report clickable probes based on the XPO1 inhibitors selinexor and eltanexor for the labeling of XPO1 in live cells to assess target engagement and selectivity. We used mass spectrometry-based chemoproteomic workflows to profile the proteome-wide selectivity of selinexor and eltanexor and show that they are highly selective for XPO1. Thermal profiling analysis of selinexor further offers an orthogonal approach to measure XPO1 engagement in live cells. We believe these probes and assays will serve as useful tools to further interrogate the biology of XPO1 and its inhibition in cellular and in vivo systems.
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- 2021
30. Direct and indirect regulation of Pom1 cell size pathway by the protein phosphatase 2C Ptc1
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Vincent Vincenzetti, Sophie G. Martin, Payal Bhatia, and Veneta Gerganova
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Cell ,Phosphatase ,Mitosis ,Cell Cycle Proteins ,Pyruvate dehydrogenase phosphatase ,Biology ,Microtubules ,Pom1 ,Microtubule ,Schizosaccharomyces ,medicine ,Protein Phosphatase 2 ,Phosphorylation ,Molecular Biology ,Cell Size ,Kinase ,Cell Membrane ,Cell Polarity ,Articles ,Cell Biology ,biology.organism_classification ,Cell biology ,Protein Phosphatase 2C ,medicine.anatomical_structure ,Schizosaccharomyces pombe ,Schizosaccharomyces pombe Proteins ,Microtubule-Associated Proteins ,Protein Kinases - Abstract
The fission yeast cells Schizosaccharomyces pombe divide at constant cell size regulated by environmental stimuli. An important pathway of cell size control involves the membrane-associated DYRK-family kinase Pom1, which forms decreasing concentration gradients from cell poles and inhibits mitotic inducers at midcell. Here, we identify the phosphatase 2C Ptc1 as negative regulator of Pom1. Ptc1 localizes to cell poles in a manner dependent on polarity and cell-wall integrity factors. We show that Ptc1 directly binds Pom1 and can dephosphorylate it in vitro but modulates Pom1 localization indirectly upon growth in low-glucose conditions by influencing microtubule stability. Thus, Ptc1 phosphatase plays both direct and indirect roles in the Pom1 cell size control pathway.
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- 2021
31. Selective Intra-Arterial Calcium Stimulation Venous Sampling Test for Preoperative Localization of Occult Neuroendocrine Tumors: Recall for an Old Technique
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Janice Newsome, Sean R. Dariushnia, Zachary L. Bercu, Nariman Nezami, Minzhi Xing, Louis G. Martin, Mangaladevi S. Patil, and Nima Kokabi
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medicine.medical_specialty ,business.industry ,Technical success ,Gastroenterology ,Stimulation ,Neuroendocrine tumors ,medicine.disease ,Occult ,030218 nuclear medicine & medical imaging ,Resection ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Venous sampling ,030220 oncology & carcinogenesis ,medicine ,Intra arterial ,Radiology, Nuclear Medicine and imaging ,Surgery ,Radiology ,business ,Pancreas - Abstract
Background Surgical resection is the curative treatment for neuroendocrine tumors (NETs). Noninvasive imaging is unreliable in localizing NETs measuring less than 2 cm. This study investigates the safety and efficacy of the selective intra-arterial calcium stimulation venous sampling test (SACST) for preoperative localization of functional NETs within the pancreas. Methods This retrospective analysis of the patients referred for localization of radiologically occult functional NETs from 2004 to 2019 was performed at a single institution. The technical success, diagnostic accuracy, and complications of the test were evaluated. Results Twenty-three patients underwent SACST. The SACST was technically successful in 100% of the patients. Lesions were successfully localized in 19 (83%) patients. Tumor blush was seen in one patient. The mean ± standard deviation of maximal dimension of the resected tumor was 2.0 ± 1.9 cm. Sensitivity, specificity, positive predictive value, and negative predictive value of the SACST for localization of all lesions were 1.0, 0.57, 0.84, and 1.0, as well as 1.0, 0.57, 0.80, and 1.0 for insulinomas, respectively. Conclusion SACST is a feasible, safe, well-tolerated, and effective procedure to preoperatively localize radiologically occult NETs within the pancreas.
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- 2021
32. Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science
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Kelly Schoch, Cecilia Esteves, Anna Bican, Rebecca Spillmann, Heidi Cope, Allyn McConkie-Rosell, Nicole Walley, Liliana Fernandez, Jennefer N. Kohler, Devon Bonner, Chloe Reuter, Nicholas Stong, John J. Mulvihill, Donna Novacic, Lynne Wolfe, Ayat Abdelbaki, Camilo Toro, Cyndi Tifft, May Malicdan, William Gahl, Pengfei Liu, John Newman, David B. Goldstein, Jason Hom, Jacinda Sampson, Matthew T. Wheeler, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J.Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Barbara N. Pusey, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J.Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C.Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Terra R. Coakley, Paul G. Fisher, Laure Fresard, Yong Huang, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, and Joy Cogan
- Subjects
Exome sequencing ,0301 basic medicine ,Computational biology ,030105 genetics & heredity ,Genome sequencing ,Article ,DNA sequencing ,Retrospective data ,03 medical and health sciences ,Rare Diseases ,Animals ,Humans ,Genomic medicine ,Medicine ,Medical diagnosis ,Exome ,Genetics (clinical) ,Retrospective Studies ,Disease gene ,business.industry ,Genomics ,030104 developmental biology ,Phenotyping ,New disease ,Undiagnosed diseases ,Ultra-rare diseases ,business - Abstract
Purpose The 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. Methods We 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. Results Of 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. Conclusion Investigations 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.
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- 2021
33. Vivid biofluorescence discovered in the nocturnal Springhare (Pedetidae)
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Adam S. Gunnelson, Sharon E. Anthony, Jonathan G. Martin, Leigh Ramon, Paula Spaeth Anich, Michaela Jurewicz, Erik R. Olson, Michaela R. Carlson, V. M. Sadagopa Ramanujam, Alissa M. Hulstrand, Allison M Kohler, and Lindsay Sears
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0106 biological sciences ,0301 basic medicine ,Old World ,Evolution ,Science ,Zoology ,Nocturnal ,Monotreme ,Evolutionary ecology ,010603 evolutionary biology ,01 natural sciences ,Biochemistry ,Article ,03 medical and health sciences ,Phylogenetics ,biology.animal ,Cuticle (hair) ,Marsupial ,Multidisciplinary ,biology ,biology.organism_classification ,030104 developmental biology ,Medicine ,Platypus ,Pedetidae - Abstract
Biofluorescence has been detected in several nocturnal-crepuscular organisms from invertebrates to birds and mammals. Biofluorescence in mammals has been detected across the phylogeny, including the monotreme duck-billed platypus (Ornithorhyncus anatinus), marsupial opossums (Didelphidae), and New World placental flying squirrels (Gluacomys spp.). Here, we document vivid biofluorescence of springhare (Pedetidae) in both museum specimens and captive individuals—the first documented biofluorescence of an Old World placental mammal. We explore the variation in biofluorescence across our sample and characterize its physical and chemical properties. The striking visual patterning and intensity of color shift was unique relative to biofluorescence found in other mammals. We establish that biofluorescence in springhare likely originates within the cuticle of the hair fiber and emanates, at least partially, from several fluorescent porphyrins and potentially one unassigned molecule absent from our standard porphyrin mixture. This discovery further supports the hypothesis that biofluorescence may be ecologically important for nocturnal-crepuscular mammals and suggests that it may be more broadly distributed throughout Mammalia than previously thought.
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- 2021
34. Are prescription misuse and illicit drug use etiologically distinct? A genetically-informed analysis of opioids and stimulants
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Arpana Agrawal, Nicholas G. Martin, Genevieve F. Dash, Michael T. Lynskey, and Wendy S. Slutske
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Drug ,medicine.medical_specialty ,Shared environment ,business.industry ,media_common.quotation_subject ,medicine.medical_treatment ,030508 substance abuse ,Twin study ,Article ,Stimulant ,03 medical and health sciences ,Psychiatry and Mental health ,0302 clinical medicine ,Opioid ,Prescription opioid ,Medicine ,Illicit drug ,030212 general & internal medicine ,Medical prescription ,0305 other medical science ,business ,Psychiatry ,Applied Psychology ,media_common ,medicine.drug - Abstract
BackgroundDrug classes are grouped based on their chemical and pharmacological properties, but prescription and illicit drugs differ in other important ways. Potential differences in genetic and environmental influences on the (mis)use of prescription and illicit drugs that are subsumed under the same class should be examined. Opioid and stimulant classes contain prescription and illicit forms differentially associated with salient risk factors (common route of administration, legality), making them useful comparators for addressing this etiological issue.MethodsA total of 2410 individual Australian twins [Mage = 31.77 (s.d. = 2.48); 67% women] were interviewed about prescription misuse and illicit use of opioids and stimulants. Univariate and bivariate biometric models partitioned variances and covariances into additive genetic, shared environmental, and unique environmental influences across drug types.ResultsVariation in the propensity to misuse prescription opioids was attributable to genes (41%) and unique environment (59%). Illicit opioid use was attributable to shared (71%) and unique (29%) environment. Prescription stimulant misuse was attributable to genes (79%) and unique environment (21%). Illicit stimulant use was attributable to genes (48%), shared environment (29%), and unique environment (23%). There was evidence for genetic influence common to both stimulant types, but limited evidence for genetic influence common to both opioid types. Bivariate correlations suggested that prescription opioid use may be more genetically similar to prescription stimulant use than to illicit opioid use.ConclusionsPrescription opioid misuse may share little genetic influence with illicit opioid use. Future research may consider avoiding unitary drug classifications, particularly when examining genetic influences.
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- 2021
35. Sharp Recanalization of Chronic Central Venous Occlusions of the Thorax Using a Steerable Coaxial Needle Technique from a Supraclavicular Approach
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Paul V. Suhocki, Jonathan G. Martin, Tony P. Smith, Charles Y. Kim, Waleska M. Pabon-Ramos, James Ronald, Alan A. Sag, and Christopher J.R. Gallo
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Thorax ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Ultrasound ,Stent ,Hemothorax ,medicine.disease ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Blunt ,Angioplasty ,Occlusion ,medicine ,Radiology, Nuclear Medicine and imaging ,Radiology ,Coaxial ,Cardiology and Cardiovascular Medicine ,business - Abstract
To evaluate the technical success and safety of a steerable coaxial sharp recanalization technique that utilizes routine needles in patients with refractory thoracic central venous occlusions. This retrospective study was performed on 36-attempted sharp recanalizations in 35 patients (mean age 50 years, 23 male) performed via a supraclavicular approach. In all cases, an 18-gauge trocar needle was custom curved to provide directional control during fluoroscopic triangulation. A 22-gauge Chiba needle was then advanced coaxially across the occlusion. A tractogram was performed to assess for traversal of unintended structures. Procedures were completed by catheter placement, angioplasty, or stenting follow successful recanalizations. Sharp recanalization using this steerable coaxial needle technique demonstrated a technical success rate of 94% (34/36). The mean occlusion length was 30 mm (range 3–53 mm). In 11 patients, success was achieved using this technique after failure of other advanced techniques. In five procedures, stent interstices were traversed. Sharp recanalization was the direct cause of one major complication consisting of pleural transgression causing mild hemothorax treated successfully with a stent graft. The proposed technique is effective and safe for patients who have failed traditional blunt recanalization techniques. Level 4, Case Series.
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- 2021
36. Long-Term Dietary Changes in Subjects with Glucose Galactose Malabsorption Secondary to Biallelic Mutations of SLC5A1
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Patricia Jardack, Shweta S. Namjoshi, Nicholas N Jackson, Martin G. Martin, Alvin P. Chan, Atrin Ardjmand, and Lisa Maloney
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Male ,Percentile ,Calorie ,glucose cotransporter ,SLC5A1 ,Physiology ,High fat ,Cardiovascular ,Oral and gastrointestinal ,Cohort Studies ,chemistry.chemical_compound ,0302 clinical medicine ,Food science ,Child ,Sodium/glucose cotransporter ,education.field_of_study ,biology ,Glucose galactose malabsorption ,Gastroenterology ,Stroke ,Glucose-galactose malabsorption ,030220 oncology & carcinogenesis ,Child, Preschool ,Cohort ,030211 gastroenterology & hepatology ,Original Article ,Female ,Carbohydrate Metabolism, Inborn Errors ,Adult ,Clinical Sciences ,Population ,Added sugar ,03 medical and health sciences ,Sodium-Glucose Transporter 1 ,Malabsorption Syndromes ,medicine ,Humans ,Obesity ,Low carbohydrate ,education ,Metabolic and endocrine ,Nutrition ,Gastroenterology & Hepatology ,business.industry ,Prevention ,Sodium ,Infant ,Fructose ,medicine.disease ,Diet ,Cross-Sectional Studies ,chemistry ,biology.protein ,Digestive Diseases ,business - Abstract
Background Glucose galactose malabsorption (GGM) is a congenital diarrheal disorder of intestinal Na+/glucose cotransport (SGLT1/SLC5A1). The required glucose and galactose-restricted diet has been well described in infancy, but long-term nutrition follow-up is limited. Aim To perform a comprehensive nutritional assessment on a cohort of patients with GGM to gain insights into the consumption patterns within the population. Methods A cross-sectional study examining dietary intake of a GGM cohort using prospective food records. The calories and nutrients of all foods, beverages, and condiments were analyzed with descriptive statistics and compared to intake patterns of age- and sex-matched NHANES groups. Results The six patients were 0.7–26 years old. Whole foods and vegetable fats were major parts of the diet, while dairy and added sweeteners were restricted. Compared to typical US intakes, mean macronutrient distribution was 88th percentile from fat, 18th percentile from carbohydrates, and 78th percentile from protein. Fructose consumption, as a proportion of total sugar intake, decreased with age, from 86.1 to 50.4%. Meanwhile, glucose consumption increased with age, from 13.8 to 48.6% of sugar intake. However, the actual amount of glucose consumed remained low, equivalent to 4th percentile of US consumption level. Galactose intake was marginal throughout life. Conclusions A GGM diet is a high-fat and high-protein/low-carbohydrate diet that is rich in fruits and vegetables but limited in dairy and added sugar. Relatively less fructose but more glucose is incorporated into the diet with age. Future studies should investigate the effects of the GGM diet on gut microbiome and long-term health. Supplementary Information The online version of this article (10.1007/s10620-020-06792-4) contains supplementary material, which is available to authorized users.
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- 2021
37. A large-scale genome-wide association study meta-analysis of cannabis use disorder
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Emma C Johnson, Ditte Demontis, Thorgeir E Thorgeirsson, Raymond K Walters, Renato Polimanti, Alexander S Hatoum, Sandra Sanchez-Roige, Sarah E Paul, Frank R Wendt, Toni-Kim Clarke, Dongbing Lai, Gunnar W Reginsson, Hang Zhou, June He, David A A Baranger, Daniel F Gudbjartsson, Robbee Wedow, Daniel E Adkins, Amy E Adkins, Jeffry Alexander, Silviu-Alin Bacanu, Tim B Bigdeli, Joseph Boden, Sandra A Brown, Kathleen K Bucholz, Jonas Bybjerg-Grauholm, Robin P Corley, Louisa Degenhardt, Danielle M Dick, Benjamin W Domingue, Louis Fox, Alison M Goate, Scott D Gordon, Laura M Hack, Dana B Hancock, Sarah M Hartz, Ian B Hickie, David M Hougaard, Kenneth Krauter, Penelope A Lind, Jeanette N McClintick, Matthew B McQueen, Jacquelyn L Meyers, Grant W Montgomery, Ole Mors, Preben B Mortensen, Merete Nordentoft, John F Pearson, Roseann E Peterson, Maureen D Reynolds, John P Rice, Valgerdur Runarsdottir, Nancy L Saccone, Richard Sherva, Judy L Silberg, Ralph E Tarter, Thorarinn Tyrfingsson, Tamara L Wall, Bradley T Webb, Thomas Werge, Leah Wetherill, Margaret J Wright, Stephanie Zellers, Mark J Adams, Laura J Bierut, Jason D Boardman, William E Copeland, Lindsay A Farrer, Tatiana M Foroud, Nathan A Gillespie, Richard A Grucza, Kathleen Mullan Harris, Andrew C Heath, Victor Hesselbrock, John K Hewitt, Christian J Hopfer, John Horwood, William G Iacono, Eric O Johnson, Kenneth S Kendler, Martin A Kennedy, Henry R Kranzler, Pamela A F Madden, Hermine H Maes, Brion S Maher, Nicholas G Martin, Matthew McGue, Andrew M McIntosh, Sarah E Medland, Elliot C Nelson, Bernice Porjesz, Brien P Riley, Michael C Stallings, Michael M Vanyukov, Scott Vrieze, Lea K Davis, Ryan Bogdan, Joel Gelernter, Howard J Edenberg, Kari Stefansson, Anders D Børglum, Arpana Agrawal, Raymond Walters, Emma Johnson, Jeanette McClintick, Alexander Hatoum, Frank Wendt, Mark Adams, Amy Adkins, Fazil Aliev, Anthony Batzler, Sarah Bertelsen, Joanna Biernacka, Tim Bigdeli, Li-Shiun Chen, Yi-Ling Chou, Franziska Degenhardt, Anna Docherty, Alexis Edwards, Pierre Fontanillas, Jerome Foo, Josef Frank, Ina Giegling, Scott Gordon, Laura Hack, Annette Hartmann, Sarah Hartz, Stefanie Heilmann-Heimbach, Stefan Herms, Colin Hodgkinson, Per Hoffman, Jouke Hottenga, Martin Kennedy, Mervi Alanne-Kinnunen, Bettina Konte, Jari Lahti, Marius Lahti-Pulkkinen, Lannie Ligthart, Anu Loukola, Brion Maher, Hamdi Mbarek, Andrew McIntosh, Matthew McQueen, Jacquelyn Meyers, Yuri Milaneschi, Teemu Palviainen, John Pearson, Roseann Peterson, Samuli Ripatti, Euijung Ryu, Nancy Saccone, Jessica Salvatore, Melanie Schwandt, Fabian Streit, Jana Strohmaier, Nathaniel Thomas, Jen-Chyong Wang, Bradley Webb, Amanda Wills, Jason Boardman, Danfeng Chen, Doo-Sup Choi, William Copeland, Robert Culverhouse, Norbert Dahmen, Benjamin Domingue, Sarah Elson, Mark Frye, Wolfgang Gäbel, Caroline Hayward, Marcus Ising, Margaret Keyes, Falk Kiefer, John Kramer, Samuel Kuperman, Susanne Lucae, Michael Lynskey, Wolfgang Maier, Karl Mann, Satu Männistö, Bertram Müller-Myhsok, Alison Murray, John Nurnberger, Aarno Palotie, Ulrich Preuss, Katri Räikkönen, Maureen Reynolds, Monika Ridinger, Norbert Scherbaum, Marc Schuckit, Michael Soyka, Jens Treutlein, Stephanie Witt, Norbert Wodarz, Peter Zill, Daniel Adkins, Dorret Boomsma, Laura Bierut, Sandra Brown, Kathleen Bucholz, Sven Cichon, E. Jane Costello, Harriet de Wit, Nancy Diazgranados, Danielle Dick, Johan Eriksson, Lindsay Farrer, Tatiana Foroud, Nathan Gillespie, Alison Goate, David Goldman, Richard Grucza, Dana Hancock, Andrew Heath, John Hewitt, Christian Hopfer, William Iacono, Eric Johnson, Jaakko Kaprio, Victor Karpyak, Kenneth Kendler, Henry Kranzler, Paul Lichtenstein, Penelope Lind, Matt McGue, James MacKillop, Pamela Madden, Hermine Maes, Patrik Magnusson, Nicholas Martin, Sarah Medland, Grant Montgomery, Elliot Nelson, Markus Nöthen, Abraham Palmer, Nancy Pederson, Brenda Penninx, John Rice, Marcella Rietschel, Brien Riley, Richard Rose, Dan Rujescu, Pei-Hong Shen, Judy Silberg, Michael Stallings, Ralph Tarter, Michael Vanyukov, Tamara Wall, John Whitfield, Hongyu Zhao, Benjamin Neale, Howard Edenberg, Technology Centre, Department of Psychology and Logopedics, Developmental Psychology Research Group, University Management, HUSLAB, Genetic Epidemiology, Institute for Molecular Medicine Finland, Department of Public Health, Centre of Excellence in Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Faculty of Arts, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Research Programs Unit, Diabetes and Obesity Research Program, Department of General Practice and Primary Health Care, Johan Eriksson / Principal Investigator, Clinicum, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, and APH - Methodology
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Risk ,Marijuana Abuse ,medicine.medical_specialty ,Alcohol abuse ,Disease ,Polymorphism, Single Nucleotide ,3124 Neurology and psychiatry ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,medicine ,Humans ,030212 general & internal medicine ,Psychiatry ,Borderline personality disorder ,Biological Psychiatry ,business.industry ,Articles ,Mental illness ,medicine.disease ,Mental health ,030227 psychiatry ,3. Good health ,Substance abuse ,Psychiatry and Mental health ,Translational science ,business ,Genome-Wide Association Study ,Psychopathology - Abstract
Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10 −9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10 −9). Cannabis use disorder and cannabis use were genetically correlated (r g 0·50, p=1·50 × 10 −21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Funding: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.
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- 2020
38. Potent Activity of an Anti-ICAM1 Antibody–Drug Conjugate against Multiple Myeloma
- Author
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Daniel W. Sherbenou, Thomas G. Martin, Olivia Perez De Acha, Byron Hann, Blake T. Aftab, Megan Murnane, Yang Su, Jeffery L. Wolf, Shelby C. Bearrows, Bin Liu, and Christopher R. Behrens
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Immunoconjugates ,medicine.medical_treatment ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Monoclonal ,Multiple myeloma ,Cancer ,Tumor ,Antibodies, Monoclonal ,Hematology ,Middle Aged ,Intercellular Adhesion Molecule-1 ,Flow Cytometry ,Antibodies, Anti-Idiotypic ,Anti-Idiotypic ,medicine.anatomical_structure ,Oncology ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Heterografts ,Female ,Development of treatments and therapeutic interventions ,Multiple Myeloma ,Biotechnology ,Adult ,Antibody-drug conjugate ,medicine.drug_class ,Oncology and Carcinogenesis ,Monoclonal antibody ,Article ,Antibodies ,Cell Line ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Oncology & Carcinogenesis ,Cell Proliferation ,Aged ,business.industry ,Daratumumab ,Immunotherapy ,medicine.disease ,ADP-ribosyl Cyclase 1 ,Orphan Drug ,030104 developmental biology ,Cancer research ,Bone marrow ,business ,Ex vivo - Abstract
Purpose: New therapies have changed the outlook for patients with multiple myeloma, but novel agents are needed for patients who are refractory or relapsed on currently approved drug classes. Novel targets other than CD38 and BCMA are needed for new immunotherapy development, as resistance to daratumumab and emerging anti-BCMA approaches appears inevitable. One potential target of interest in myeloma is ICAM1. Naked anti-ICAM1 antibodies were active in preclinical models of myeloma and safe in patients, but showed limited clinical efficacy. Here, we sought to achieve improved targeting of multiple myeloma with an anti-ICAM1 antibody–drug conjugate (ADC). Experimental Design: Our anti-ICAM1 human mAb was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines in vitro, orthotopic xenografts in vivo, and patient samples ex vivo. The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state. Results: The anti-ICAM1 ADC displayed potent anti-myeloma cytotoxicity in vitro and in vivo. In addition, we have verified that ICAM1 is highly expressed on myeloma cells and shown that its expression is further accentuated by the presence of bone marrow microenvironmental factors. In primary samples, ICAM1 is differentially overexpressed on multiple myeloma cells compared with normal cells, including daratumumab-refractory patients with decreased CD38. In addition, ICAM1-ADC showed selective cytotoxicity in multiple myeloma primary samples. Conclusions: We propose that anti-ICAM1 ADC should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma.
- Published
- 2020
39. Cellular Source of Cysteinyl Leukotrienes Following Chlorine Exposure
- Author
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Toby K. McGovern, Soroor Farahnak, Satoshi Ano, James G. Martin, and Sarah McCuaig
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Chemistry ,Phagocytosis ,Clinical Biochemistry ,Airway hyperresponsiveness ,chemistry.chemical_element ,CHLORINE EXPOSURE ,Cell Biology ,respiratory system ,Pharmacology ,medicine.disease_cause ,respiratory tract diseases ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030228 respiratory system ,Cysteinyl leukotrienes ,polycyclic compounds ,Chlorine ,medicine ,Molecular Biology ,Oxidative stress - Abstract
Exposure of mice to high concentrations of chlorine leads to the synthesis of cysteinyl leukotrienes (cysLTs). CysLTs contribute to chlorine-induced airway hyperresponsiveness. The aim of the curre...
- Published
- 2020
40. Predictors of State-Level Stay-at-Home Orders in the United States and Their Association With Mobility of Residents
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Philip Gigliotti and Erika G. Martin
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Male ,medicine.medical_specialty ,Physical Distancing ,Pneumonia, Viral ,Population ,Public Policy ,Betacoronavirus ,03 medical and health sciences ,Tax revenue ,0302 clinical medicine ,Per capita ,medicine ,Humans ,030212 general & internal medicine ,education ,Pandemics ,health care economics and organizations ,Travel ,education.field_of_study ,030505 public health ,SARS-CoV-2 ,Health Policy ,Public health ,Social distance ,Hazard ratio ,Public Health, Environmental and Occupational Health ,COVID-19 ,United States ,Geography ,Quarantine ,Geographic Information Systems ,Household income ,Female ,Coronavirus Infections ,0305 other medical science ,Medicaid ,Demography - Abstract
Objective To evaluate predictors of stay-at-home order adoption among US states, as well as associations between order enactment and residents' mobility. Design We assess associations between state characteristics and adoption timing. We also assess associations between enactment and aggregate state-level measures of residents' mobility (Google COVID-19 Community Mobility Reports). Setting The United States. Participants Adoption population: 50 US states and District of Columbia. Mobility population: state residents using devices with GPS tracking accessible by Google. Intervention and exposures State characteristics: COVID-19 diagnoses per capita, 2016 Trump vote share, Republican governor, Medicaid expansion status, hospital beds per capita, public health funding per capita, state and local tax revenue per capita, median household income, population, percent residents 65 years or older, and percent urban residents. Mobility exposure: indicator of order enactment by March 29, 2020 (date of mobility data collection). Main outcome measures Order adoption timing: days since adoption of first order. Mobility: changes in mobility to 6 locations from February 6 to March 29, 2020. Results In bivariate models, order adoption was associated with COVID-19 diagnoses (hazard ratio [HR] = 1.01; 95% confidence interval [CI], 1.00 to 1.01), Republican governor (HR = 0.24; 95% CI, 0.13 to 0.44), Medicaid expansion (HR = 2.50; 95% CI, 1.40 to 4.48), and hospital capacity (HR = 0.43; 95% CI, 0.26 to 0.70), consistent with findings in the multivariate models. Order enactment was positively associated with time at home (beta (B) = 1.31; 95% CI, 0.35 to 2.28) and negatively associated with time at retail and recreation (B = -7.17; 95% CI, -10.89 to -3.46) and grocery and pharmacy (B = -8.28; 95% CI, -11.97 to -4.59) locations. Trump vote share was associated with increased mobility for 4 of 6 mobility measures. Conclusions and relevance While politics influenced order adoption, public health considerations were equally influential. While orders were associated with decreased mobility, political ideology was associated with increased mobility under social distancing policies.
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- 2020
41. Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information
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Alma Dzubur Kulenovic, Michael J. Lyons, Elizabeth A. Bolger, Kenneth J. Ruggiero, Zhewu Wang, Laramie E. Duncan, Bozo Lugonja, Joanne Voisey, José Miguel Caldas-de-Almeida, Regina E. McGlinchey, Laura J. Bierut, Michael A. Hauser, Jean C. Beckham, Dan J. Stein, Alexander C. McFarlane, Elbert Geuze, Victoria B. Risbrough, Douglas Maurer, Christy A. Denckla, Seth G. Disner, William P. Milberg, Erika J. Wolf, Scott R. Sponheim, Caroline M. Nievergelt, Henry R. Kranzler, Clement C. Zai, Antonia V. Seligowski, Miro Jakovljević, Katharina Domschke, Paul A. Arbisi, Thomas Werge, Vasiliki Michopoulos, Joel Gelernter, Sarah D. Linnstaedt, Nastassja Koen, Sonya B. Norman, Nicholas G. Martin, Janine D. Flory, Meghan M Brashear, Melissa A. Polusny, Nathan A. Kimbrel, Douglas L. Delahanty, Milissa L. Kaufman, Peter Roy-Byrne, Magali Haas, Monica Uddin, Matig R. Mavissakalian, William S. Kremen, Ole A. Andreassen, Marco P. Boks, Matthew S. Panizzon, Christiaan H. Vinkers, Bart P. F. Rutten, Heather Lasseter, Richard A. Shaffer, Aferdita Goci, Jessica L. Maples-Keller, Israel Liberzon, Melanie E. Garrett, Alicia K. Smith, Catrin Lewis, Dewleen G. Baker, Murray B. Stein, Xuejun Qin, Nikolaos P. Daskalakis, Sherry Winternitz, Douglas E. Williamson, Alex O. Rothbaum, David Forbes, Leigh van den Heuvel, Scott D. Gordon, Edward J. Trapido, Marti Jett, Ole Mors, Adam X. Maihofer, Christina M. Sheerin, Lori A. Zoellner, A.C. Bustamante, David M. Hougaard, Alexandra Evans, Chia-Yen Chen, Robert H. Pietrzak, Rachel Yehuda, Allison C. Provost, Matthew Peverill, Aarti Gautam, Bruce R. Lawford, Derrick Silove, Bekh Bradley, Gerome Breen, Charles F. Gillespie, Allison E. Ashley-Koch, Kerry J. Ressler, Christiane Wolf, Renato Polimanti, Jonathan Ian Bisson, Adriana Lori, Lynn M. Almli, Norah C. Feeny, Jonas Bybjerg-Grauholm, Guia Guffanti, Søren Bo Andersen, Anders D. Børglum, Elizabeth Ketema, Andrea L. Roberts, Marie Bμkvad-Hansen, Ross McD. Young, Jürgen Deckert, Jonathan Sebat, Rajendra A. Morey, P. B. Mortensen, Lindsay A. Farrer, Yunpeng Wang, Karestan C. Koenen, Joseph R. Calabrese, Bizu Gelaye, Jurjen J. Luykx, Andrew Ratanatharathorn, Charles P. Morris, S. Bryn Austin, Miranda Van Hooff, Edward S. Peters, Katie A. McLaughlin, Anthony P. King, Jonathan R. I. Coleman, Holly K. Orcutt, Keith A. Young, Samuel A. McLean, Jennifer S. Stevens, Rasha Hammamieh, Robert J. Ursano, Mark W. Miller, Allison E. Aiello, Charles R. Marmar, Esmina Avdibegović, Katy Torres, Elliot C. Nelson, Rany M. Salem, Martin H. Teicher, Rebecca Mellor, Karen-Inge Karstoft, Aliza P. Wingo, Alaptagin Khan, Michelle A. Williams, Dick Schijven, Merete Nordentoft, Ananda B. Amstadter, Shareefa Dalvie, Michelle F. Dennis, Mark J. Daly, Mark W. Logue, Soraya Seedat, Julia S. Seng, Carol E. Franz, Stephan Ripke, Karmel W. Choi, Sandro Galea, Richard A. Bryant, Ian Jones, Anders M. Dale, Wesley K. Thompson, Lauren A.M. Lebois, Sixto E. Sanchez, Ronald C. Kessler, Tanja Jovanovic, Divya Mehta, Jordan W. Smoller, Eric O. Johnson, John P. Rice, Andrew C. Heath, Nancy L. Saccone, Barbara O. Rothbaum, Alan L. Peterson, Meaghan O'Donnell, Sian M. J. Hemmings, Eric Vermetten, Dragan Babić, Hongyu Zhao, Tianying Wu, Christopher R. Erbes, Ariane Rung, NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM), Centro de Estudos de Doenças Crónicas (CEDOC), Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, MUMC+: MA Psychiatrie (3), Anatomy and neurosciences, Psychiatry, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
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Oncology ,Multivariate analysis ,LD SCORE REGRESSION ,Genome-wide association study ,THOUSANDS ,Medical and Health Sciences ,Stress Disorders, Post-Traumatic ,GWAS ,Stress Disorders ,Psychiatry ,Genome-Wide Association Study / methods ,Traumatic stress ,PROLIFERATION ,PTSD ,Single Nucleotide ,Biological Sciences ,Post-Traumatic Stress Disorder (PTSD) ,Anxiety Disorders ,Mental Health ,Phenotype ,Cohort ,Polymorphism, Single Nucleotide / genetics ,medicine.medical_specialty ,Stress Disorders, Post-Traumatic / genetics ,Quantitative trait locus ,Polymorphism, Single Nucleotide ,Genetic correlation ,behavioral disciplines and activities ,Trauma ,Heritability ,Internal medicine ,PSYCHIATRIC GENOMICS ,mental disorders ,medicine ,Genetics ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,GENOME-WIDE ASSOCIATION ,METAANALYSIS ,Biological Psychiatry ,Genetic association ,business.industry ,Prevention ,Human Genome ,Psychology and Cognitive Sciences ,PheWAS ,Brain Disorders ,Post-Traumatic ,RISK-FACTORS ,business ,Genome-Wide Association Study - Abstract
Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological Psychiatry Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods. publishersversion published
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- 2022
42. Identifying the Common Genetic Basis of Antidepressant Response
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Sara A. Paciga, Richard M. Weinshilboum, Andrew M. McIntosh, Tim B. Bigdeli, Stephanie H. Witt, Sven Cichon, Glyn Lewis, Henning Teismann, Brenda W.J.H. Penninx, Gerome Breen, Roseann E. Peterson, Saira Saeed Mirza, Diego Albani, Lisa Jones, Andreas J. Forstner, Sara Mostafavi, Julien Bryois, Qingqin S. Li, Kenneth S. Kendler, Thomas Damm Als, Fernando S. Goes, Marie Bækvad-Hansen, Nancy L. Pedersen, Gianluigi Forloni, Per Qvist, Carsten Horn, Per Hoffmann, Steven P. Hamilton, Georg Homuth, Michael Gill, Julien Mendlewicz, Katharina Domschke, Volker Arolt, Adrian I. Campos, Christine Søholm Hansen, Scott D. Gordon, Hogni Oskarsson, Peter McGuffin, Oliver Pain, Eric Jorgenson, Victoria S. Marshe, Stacy Steinberg, Bertram Müller-Myhsok, Mark Adams, J. Raymond DePaulo, Rick Jansen, Katherine J. Aitchison, Vassily Trubetskoy, Henry Völzke, Manuel Mattheisen, Bernard Ng, James A. Knowles, Dorret I. Boomsma, Tracy Air, Elisabeth B. Binder, Ian B. Hickie, Christel M. Middeldorp, Tõnu Esko, David M. Hougaard, E.J.C. de Geus, Toni-Kim Clarke, Helena Gaspar, Bernhard T. Baune, Abdel Abdellaoui, Engilbert Sigurdsson, Andres Metspalu, Klaus Berger, Jorge A. Quiroz, Patrick F. Sullivan, Aartjan T.F. Beekman, Thomas Hansen, Panagiotis Ferentinos, Jürgen Wellmann, Miguel E. Rentería, Daniel Umbricht, Marcella Rietschel, Stanley I. Shyn, Chiara Fabbri, Hreinn Stefansson, Jerome C. Foo, Daniel Souery, Zoltán Kutalik, Yu-Li Liu, Paul F. O'Reilly, Michael John Owen, Nese Direk, Douglas F. Levinson, Stuart Montgomery, Hamdi Mbarek, David M. Howard, Guido Bondolfi, Lucía Colodro-Conde, Pippa A. Thomson, Merete Nordentoft, Stefan Kloiber, Yunpeng Wang, Michael Conlon O'Donovan, Grant C.B. Sinnamon, Alexander Viktorin, Hilary K. Finucane, Esben Agerbo, Stefan Herms, Markus M. Nöthen, Till F. M. Andlauer, Divya Mehta, Bradley T. Webb, Joanna M. Biernacka, David J. Porteous, Jordan W. Smoller, Jonathan R. I. Coleman, Dean F. MacKinnon, Farnush Farhadi Hassan Kiadeh, Baptiste Couvy-Duchesne, Evelin Mihailov, Eleanor M. Wigmore, Franziska Degenhardt, Jianxin Shi, Dale R. Nyholt, Enda M. Byrne, Stephan Ripke, Ole Mors, Patrik K. E. Magnusson, Eric J. Lenze, Warren W. Kretzschmar, Masaki Kato, Marcus Ising, Ian Jones, Lynsey S. Hall, Wouter J. Peyrot, Ling Shen, Nader Perroud, Na Cai, Maciej Trzaskowski, Matthias Nauck, Isaac S. Kohane, Enrico Domenici, Fabian Streit, James L. Kennedy, Peter M. Visscher, Valentina Escott-Price, Donald J. MacIntyre, Enrique Castelao, Margarita Rivera, Mojca Z. Dernovsek, John P. Rice, Joseph Zohar, Gail Davies, Andrew C. Heath, Josef Frank, Wesley K. Thompson, Caroline Hayward, Penelope A. Lind, Thorgeir E. Thorgeirsson, Rudolf Uher, Jana Strohmaier, Henriette N. Buttenschøn, Erin C. Dunn, Jonas Bybjerg-Grauholm, Alexander Teumer, Jakob Grove, Eske M. Derks, Nicholas G. Martin, Jodie N. Painter, Myrna M. Weissman, Preben Bo Mortensen, Michel G. Nivard, Catherine Schaefer, Yihan Li, Daniel J. Smith, Shih-Jen Tsai, Niamh Mullins, Jian Yang, Marianne Giørtz Pedersen, Dan Rujescu, Thomas G. Schulze, Lili Milani, Yuri Milaneschi, Giorgio Pistis, James B. Potash, Neven Henigsberg, Nicholas John Craddock, Karen Hodgson, Silviu-Alin Bacanu, Shantel Weinsheimer, Charles F. Reynolds, Johannes H. Smit, Gonneke Willemsen, Futao Zhang, Henning Tiemeier, Grant W. Montgomery, Martin Preisig, Udo Dannlowski, Thalia C. Eley, Thomas Werge, Katherine E. Tansey, Jane H. Christensen, Julia Kraft, Ian J. Deary, Cathryn M. Lewis, Sarah E. Medland, André G. Uitterlinden, Daniel J. Müller, Carsten Bøcker Pedersen, Gustavo Turecki, Hans J. Grabe, Matthew Traylor, Brien P. Riley, Roy H. Perlis, Patrick J. McGrath, Conor V. Dolan, Hualin S. Xi, Jonathan Marchini, Robert A. Schoevers, Albert M. van Hemert, Anders D. Børglum, Susanne Lucae, Jouke-Jan Hottenga, Kari Stefansson, Benoit H. Mulsant, Francis M. Mondimore, Naomi R. Wray, Yang Wu, Wolfgang Maier, Danielle Posthuma, Annamaria Cattaneo, Gregory E. Crawford, Siegfried Kasper, Alessandro Serretti, Tania Carrillo-Roa, Robert Maier, Pamela A. F. Madden, Eva C. Schulte, Jens Treutlein, Joanna Hauser, Sandra Van der Auwera, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, APH - Methodology, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Adult Psychiatry, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Epidemiology, Child and Adolescent Psychiatry / Psychology, and Internal Medicine
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Oncology ,MDD ,medicine.medical_specialty ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Antidepressant response ,Depression ,GWAS ,Genetics ,Polygenic score ,SDG 3 - Good Health and Well-being ,Internal medicine ,Genetic variation ,medicine ,ddc:610 ,Genetic association ,General Medicine ,Heritability ,medicine.disease ,Schizophrenia ,Sample size determination ,Settore BIO/14 - Farmacologia ,Major depressive disorder - Abstract
Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction.Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response.Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.
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- 2022
43. Isatuximab plus carfilzomib and dexamethasone in East Asian patients with relapsed multiple myeloma: IKEMA subgroup analysis
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Tanaka Junji, Sung-Hyun Kim, Jin Seok Kim, Youngil Koh, Kenichi Ishizawa, Thomas G. Martin, Yvonne Dong, Marie-Laure Risse, Philippe Moreau, Kenshi Suzuki, Chang-Ki Min, Michihiro Uchiyama, Kihyun Kim, Shigeki Ito, and Yawara Kawano
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Oncology ,Isatuximab ,Cancer Research ,medicine.medical_specialty ,business.industry ,Subgroup analysis ,Hematology ,medicine.disease ,Antibodies, Monoclonal, Humanized ,Carfilzomib ,Dexamethasone ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,business ,Multiple Myeloma ,Oligopeptides ,Multiple myeloma ,medicine.drug - Abstract
e20015 Background: The Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) plus carfilzomib and dexamethasone (Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (hazard ratio [HR] 0.53; 99% confidence interval [CI] 0.32–0.89; P= 0.0007). We evaluated the efficacy and safety of Isa-Kd in the East Asian patients (19 Japanese, 27 Korean). Methods: RMM pts who received 1-3 prior lines of therapy were stratified to receive Isa-Kd or Kd. Isa-Kd arm received Isa (10 mg/kg intravenously) weekly for 4 weeks, then every 2 weeks. Both arms received K (20 mg/m2 days 1-2, 56 mg/m2 thereafter) twice-weekly for 3 of 4 weeks, and d (20 mg) twice-weekly. Treatment continued until disease progression or unacceptable adverse events (AE). The primary endpoint was prolongation of PFS. Key secondary endpoints included; very good partial response or better (≥VGPR), complete response (CR) rate and minimal residual disease negativity (MRD–) rate. Results: East Asian pts (25 Isa-Kd, 21 Kd) were randomized. Pt characteristics were similar in the East Asian subgroup compared with the intent to treat (ITT) population (N = 302). Median age (Isa-Kd 64.0 [range 45–83] years vs Kd 60.0 [range 33–73] years); median prior lines Isa-Kd 2.0 (range 1–3) vs Kd 1.0 (range 1–3); refractory to lenalidomide 16.0% Isa-Kd vs 47.6% Kd; refractory to PI 20.0% Isa-Kd vs 33.3% Kd; high-risk cytogenetics 48.0% Isa-Kd vs 42.9% Kd. After a median follow-up of 20.7 months, the addition of Isa to Kd improved ≥VGPR, CR and MRD– rates (Table). The HR 0.64 (95%CI: 0.231-1.764) for disease progression or death favored Isa-Kd. Grade ≥3 AEs were observed in 79.2% Isa-Kd vs 55.0% Kd pts, serious TEAEs in 45.8% Isa-Kd vs 50.0% Kd; TEAEs leading to treatment discontinuation were lower in the Isa-Kd group (4.2% Isa-Kd vs 10.0% Kd). Overall, 64.0% Isa-Kd vs 42.9% Kd pts were still receiving treatment. Conclusions: Efficacy and safety results of Isa-Kd in East Asian pts are consistent with the results of the overall IKEMA population, in which significantly better efficacy (PFS, CR, ≥VGPR and MRD– rate) was reported in favor of Isa-Kd without an increase in the number of patients with serious TEAEs or discontinuations. Isa-Kd is a potential treatment option for East Asian pts with RMM. Clinical trial information: NCT03275285. [Table: see text]
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- 2022
44. Dal‐induced red blood cell incompatibilities in a Doberman Pinscher with von Willebrand factor deficiency and ehrlichiosis
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K. Jane Wardrop, Andreza Conti-Patara, Thandeka R. Ngwenyama, and Linda G. Martin
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Male ,Erythrocytes ,040301 veterinary sciences ,Anemia ,Blood Donors ,0403 veterinary science ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Von Willebrand factor ,hemic and lymphatic diseases ,von Willebrand Factor ,Prevalence ,Von Willebrand disease ,medicine ,Animals ,Blood Transfusion ,Dog Diseases ,Whole blood ,Blood type ,General Veterinary ,biology ,business.industry ,Ehrlichiosis ,030208 emergency & critical care medicine ,04 agricultural and veterinary sciences ,medicine.disease ,Anti-Bacterial Agents ,Doberman Pinscher ,von Willebrand Diseases ,medicine.anatomical_structure ,Blood Grouping and Crossmatching ,Blood Group Incompatibility ,Doxycycline ,Immunology ,Ehrlichiosis (canine) ,Blood Group Antigens ,biology.protein ,Bone marrow ,business - Abstract
Objective To describe a complex case involving the management of a dog with von Willebrand disease (vWD), active ehrlichiosis infection, nonregenerative anemia, and blood type incompatibility related to the Dal antigen. Case summary A 13-week-oldintact male Doberman Pinscher weighing 7.2 kg was presented to the emergency service for a previous hemorrhaging event and progressive nonregenerative anemia. The dog had received a fresh whole blood transfusion 8 days prior to presentation due to severe anemia. Upon presentation, the puppy was tachycardic, and his mucous membranes were pale. A CBC revealed a nonregenerative anemia with a PCV of 0.11 L/L (11%). von Willebrand factor deficiency was suspected and later confirmed. The dog's blood type was dog erythrocyte antigen (DEA) 1 positive, but cross-matching to 4 RBC units, both DEA 1 positive and negative, failed to yield any compatible units. Antibody against a possible Dal RBC antigen was suspected, and 11 blood donors (Dalmatians and Dobermans) were cross-matched to find 2 compatible donors. After an uneventful fresh whole blood transfusion, a bone marrow biopsy revealed a hypocellular bone marrow and erythroid hypoplasia. A SNAP4DxPlus test and subsequent polymerase chain reaction (PCR) testing were positive for Ehrlichia ewingii and E. canis. Treatment with doxycycline was started, and the PCV was 0.17 L/L (17%) at discharge. At the 1-week follow-up, the PCV was 0.24 L/L (24%), and the puppy was doing well. New or unique information provided This is a unique case of a dog presenting with several challenging disorders, including vWD resulting in hemorrhage, ehrlichiosis potentially contributing to a nonregenerative anemia, and a blood type incompatibility due to the Dal antigen. Doberman Pinschers have a high prevalence of vWD- and Dal-negative phenotype, which emphasizes the value of cross-matching and the recognition of antigen prevalence in specific breeds.
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- 2020
45. Sex differences in the relative influence of marital status and parenthood on alcohol use disorder symptoms: A multilevel discordant twin design
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Nicholas G. Martin, Genevieve F. Dash, Michael T. Lynskey, and Wendy S. Slutske
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Adult ,Male ,Parents ,Alcohol Drinking ,Twins ,Context (language use) ,Alcohol use disorder ,Article ,medicine ,Humans ,Big Five personality traits ,Biological Psychiatry ,Sex Characteristics ,Pregnancy ,Discordant Twin ,Marital Status ,Parental status ,Causal effect ,Australia ,medicine.disease ,Alcoholism ,Clinical Psychology ,Psychiatry and Mental health ,Marital status ,Female ,Psychology ,Demography - Abstract
Marriage and parenthood are associated with alcohol use and use disorder (AUD), although they are confounded such that many studies struggle to identify their unique and/or causal effects. The present study utilized a genetically-informed discordant twin design that strengthens the putative causal role of marital and parental status in the presentation of AUD symptoms by using each individual’s co-twin as their own control while simultaneously modeling both predictors among men and women. Participants were 980 complete same-sex twin pairs from the Australian Twin Registry (M(age)=31.70 [SD=2.48]; 71% women). Marital status, parental status, and past year AUD symptoms were assessed via semi-structured interview. Three random-intercept generalized linear mixed models were fit in men and women including 1) marital status only, 2) parental status only, and 3) both marital and parental status; demographics, past year pregnancy, age of first drink, age of regular drinking, personality traits, and antisociality were included as covariates. Models tested for quasi-causal and familial effects. The sole-predictor marital status model (model 1) provided the best fit among men, while the simultaneous-predictor marital and parental status model (model 3) provided the best fit among women. Sole-predictor models showed familial effects of both predictors among men, and quasi-causal and familial effects of both predictors among women; the simultaneous-predictor model revealed familial effects of marital status only among men, and quasi-causal effects of parental status only among women. The present study elucidates important sex differences in the presentation of AUD among midlife adults in the context of notable developmental milestones.
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- 2020
46. Asthma and fixed airflow obstruction: Long‐term trajectories suggest distinct endotypes
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James G. Martin, Ronald Olivenstein, Qutayba Hamid, Catherine Lemière, Benjamin M. Smith, and Nan Zhao
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Adult ,Male ,0301 basic medicine ,Spirometry ,medicine.medical_specialty ,Sputum Cytology ,Exacerbation ,Immunology ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Forced Expiratory Volume ,Internal medicine ,Epidemiology ,medicine ,Humans ,Immunology and Allergy ,Glucocorticoids ,Asthma ,medicine.diagnostic_test ,business.industry ,digestive, oral, and skin physiology ,Middle Aged ,respiratory system ,Eosinophil ,medicine.disease ,Bronchodilator Agents ,respiratory tract diseases ,Airway Obstruction ,030104 developmental biology ,medicine.anatomical_structure ,030228 respiratory system ,Asthma Control Questionnaire ,Disease Progression ,Quality of Life ,Airway Remodeling ,Leukotriene Antagonists ,Sputum ,Female ,medicine.symptom ,business ,Follow-Up Studies - Abstract
BACKGROUND Long-term trajectories of asthma with fixed airflow obstruction (FAO) may reveal links to inflammatory endotypes. OBJECTIVE We investigated whether measures of asthma control and airway inflammation and remodelling differed by long-term FAO status in moderate-to-severe asthma. METHODS Adults enrolled in the Difficult Asthma Study assessed initially using serial Asthma Control Questionnaire (ACQ), exacerbation history, spirometry and sputum cytology over 12 months, as well as endoscopic bronchial biopsy with airway smooth muscle (ASM) quantification, were revaluated three or more years later with questionnaires and spirometry. FAO was defined as a persistent post-bronchodilator forced expired volume in one second (FEV1 )-to-forced vital capacity ratio below 0.70. RESULTS Sixty-two participants (mean ± SD age 48 ± 11 years; 50% female; 75% atopic; asthma duration 24 ± 14 years) returned for follow-up assessment (median interval 7.9 years; IQR: 5.4-8.8 years). Compared to participants without FAO (n = 28), those with FAO at baseline and long-term follow-up (n = 18) had higher baseline sputum neutrophil content and ASM, and a higher exacerbation frequency that persisted at long-term follow-up. Sputum eosinophils, ACQ and long-term FEV1 decline did not differ. Participants with incident FAO at long-term follow-up (n = 16) had higher baseline exacerbation frequency, sputum eosinophil content, higher ACQ scores and greater decline in FEV1 , whereas baseline ASM was similar to those without FAO. CONCLUSION In moderate-to-severe asthma, long-term FAO is characterized by neutrophilic sputum inflammation and airway remodelling, but FEV1 decline is similar to those without FAO. Long-term incident FAO is preceded by higher exacerbation frequency, higher sputum eosinophil content and significant FEV1 decline.
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- 2020
47. Childhood maltreatment and disordered gambling in adulthood: disentangling causal and familial influences
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Nicholas G. Martin, Genevieve F. Dash, and Wendy S. Slutske
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Adult ,Male ,050103 clinical psychology ,Twins ,Alcohol use disorder ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,0501 psychology and cognitive sciences ,Child Abuse ,Child ,Association (psychology) ,Applied Psychology ,Maladaptation ,Discordant Twin ,05 social sciences ,Multilevel model ,Australia ,medicine.disease ,Twin study ,Educational attainment ,Zygosity ,030227 psychiatry ,Alcoholism ,Psychiatry and Mental health ,Gambling ,Female ,Psychology ,Clinical psychology - Abstract
BackgroundDespite abundant research on the potential causal influence of childhood maltreatment (CM) on psychological maladaptation in adulthood, almost none has implemented the discordant twin design as a means of examining the role of such experiences in later disordered gambling (DG) while accounting for genetic and family environmental confounds. The present study implemented such an approach to disentangle the potential causal and familial factors that may account for the association between CM and DG.MethodsParticipants were 3750 twins from the Australian Twin Registry [Mage = 37.60 (s.d. = 2.31); 58% female]. CM and DG were assessed separately via two semi-structured telephone interviews. Random-intercept generalized linear mixed models were fit to the data; zygosity, sex, educational attainment, childhood psychiatric disorder, adult antisocial behavior, and alcohol use disorder (AUD) were included as covariates.ResultsNeither quasi-causal nor familial effects of CM predicted DG after adjusting for covariates. Educational attainment appeared to reduce the risk of DG while AUD appeared to increase risk; evidence also emerged for familial effects of antisocial behavior on DG. Post-hoc analyses revealed a familial effect of CM on antisocial behavior, indicating that the association between CM and DG identified in unadjusted models and in prior studies may be accounted for by genetic and shared family environmental effects of antisociality.ConclusionsThese findings add to the meager literature showing that CM does not exert a causal effect on DG, and present novel evidence that familial effects of antisocial behavior may account for the association between CM and DG identified in extant non-twin research.
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- 2020
48. Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder
- Author
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Katherine Wesseling Perry, Archana Raja, Emilie D. Douine, Xue Zhong Liu, Brent L. Fogel, Stan F. Nelson, Kenneth R. Maravilla, Eva H. Baker, Dave Viskochil, Kerstin Kutsche, Jordan H. Whitlock, Susan L. Samson, Christine M. Eng, Chloe M. Reuter, Suman Jayadev, David R. Adams, Sihoun Hahn, Rebecca C. Spillmann, Margaret Adam, Heather C Mefford, John C. Carey, Ehsan Ghayoor Karimiani, Donna M. Krasnewich, David Goldstein, Susan A. Korrick, Guoyun Yu, Tomas Honzik, Henry Houlden, Andrea L. Gropman, David A. Sweetser, Anna Bican, Carlos A. Bacino, Liliana Fernandez, Gabrielle Brown, Justin Alvey, Hane Lee, Emanuele G. Coci, Hongzheng Dai, Mario Saporta, Laurel A. Cobban, John F. Bohnsack, Stephanie Fox, Heidi Cope, Tyra Estwick, Lorraine Potocki, Nichole Hayes, Elizabeth A. Burke, Rizwan Hamid, Aaron R. Quinlan, Kelly Hassey, Lindsay C. Burrage, Jane Juusola, Adeline Vanderver, Malik Alawi, Teri A. Manolio, Maja Hempel, Esther M. Maier, Jennifer Kennedy, Bruce D. Gelb, Martha Horike-Pyne, Amarilis Sanchez-Valle, Euan A. Ashley, Surendra Dasari, Elizabeth Blue, Eva Morava-Kozicz, Natalie Rosenwasser, Alan H. Beggs, Bryn D. Webb, Isaac S. Kohane, Kelly Schoch, C. Christopher Lau, Nicole M. Walley, Laura M. Amendola, Genecee Renteria, Catherine H. Sillari, Jonathan A. Bernstein, Pinar Bayrak-Toydemir, R. Frank Kooy, Mariko Nakano-Okuno, Manuela Siekmeyer, Marije E. C. Meuwissen, Stephanie Bivona, Mark Wener, Precilla D'Souza, Olveen Carrasquillo, Paolo Moretti, Diane B. Zastrow, David J. Eckstein, Janet S. Sinsheimer, Kathy Sisco, Holly K. Tabor, William E. Byrd, Esteban C. Dell'Angelica, Rosario Isasi, Jacinda B. Sampson, Carsten Bonnenmann, J. Lawrence Merritt, Joan M. Stoler, Richard L. Maas, Paul G. Fisher, Jeanette C. Papp, Kimberly LeBlanc, Lilianna Solnica-Krezel, Mustafa Tekin, Mathias Woidy, Andrew B. Crouse, Katleen Ballon, David Murphy, Matthew T. Wheeler, Joseph Loscalzo, Ellen Macnamara, Cecelia P. Tamburro, Lefkothea P. Karaviti, Chunli Zhao, Ingrid A. Holm, Pankaj B. Agrawal, Alana L. Grajewski, Stephen C. Pak, Ian R. Lanza, Mohammad Doosti, Jennifer E. Posey, Rebecca Signer, Katie Golden-Grant, Christopher A. Walsh, Alica M. Goldman, Jyoti G. Dayal, Queenie K.-G. Tan, Martin G. Martin, Joy D. Cogan, Kevin S. Smith, Deborah A. Nickerson, Elisabeth McGee, Laure Fresard, Rena A. Godfrey, Sharyn A. Lincoln, Kathleen E. Sullivan, Mariska Davids, Melissa A. Walker, Prashant Sharma, Maria Iascone, Neil H. Parker, Carlos Ferreira, Elizabeth L. Fieg, Edwin K. Silverman, Michael L. Cunningham, Pengfei Liu, Edward M. Behrens, Sandra K. Loo, David R. Murdock, F. Sessions Cole, C. Ron Scott, Dan Doherty, Elly Brokamp, John H. Newman, Alden Y. Huang, Laura A. Pace, Avi Nath, Jimmy Bennet, Georg Christoph Korenke, Alyssa A. Tran, Gabriel F. Batzli, Jimann Shin, Matthew A. Deardorff, Naghmeh Dorrani, Diane Beysen, Irma Gutierrez, Stanislav Kmoch, Majid Alfadhel, Fred F. Telischi, Jennifer A. Sullivan, William A. Gahl, María Palomares-Bralo, Gerard T. Berry, Colleen E. McCormack, Lance H. Rodan, Reza Maroofian, Lenka Nosková, Judy Schaechter, Lynne A. Wolfe, Deborah Krakow, Daryl A. Scott, Tara Wenger, Jason Hom, Dustin Baldridge, Lynette Rives, Lee-kai Wang, Dawn L. Earl, Ralph L. Sacco, Fernando Santos-Simarro, Irman Forghani, Fuki M. Hisama, Terra R. Coakley, Hsiao-Tuan Chao, Jeremy D. Woods, Emily G. Kelley, Jean M. Johnston, Neil A. Hanchard, Amy K. Robertson, Matt Velinder, Byron L. Lam, Wendy H. Raskind, William J. Craigen, Stephan Züchner, Guney Bademci, Julian A. Martinez-Agosto, Mary Koziura, Beth A. Martin, Angela Sun, John A. Phillips, Seema R. Lalani, Daniela Buhas, Emily Solem, Gary D. Clark, Gill Bejerano, Ingo Kurth, Deborah Barbouth, Tiina K. Urv, Fanny Kortüm, Ian A. Glass, Ta Chen Peter Chang, Yong Huang, Roy C. Levitt, Paola Francesca Ajmone, Brenna Boyd, René Santer, Tim Schedl, David D. Draper, Ghayda M. Mirzaa, Aroa Rodríguez Alonso, Stephanie Wallace, Colleen E. Wahl, Calum A. MacRae, Gail P. Jarvik, Jacob L. McCauley, Jill A. Rosenfeld, Ronit Marom, Monte Westerfield, Matthew Might, Poupak Javaher-Haghighi, Brendan C. Lanpher, Devon Bonner, Cynthia J. Tifft, Cecilia Esteves, May Christine V. Malicdan, Jim Bale, Fariha Jamal, Nicola Longo, Christina G.S. Palmer, Lisa Emrick, Peter H. Byers, Vandana Shashi, Tiphanie P. Vogel, Richard A. Lewis, Jijun Wan, Barbara N. Pusey, Maria T. Acosta, Jaak Jaeken, Allyn McConkie-Rosell, Shirley Sutton, John Yang, Lorenzo D. Botto, Hilde Peeters, Rong Mao, Catherine Groden, Brendan Lee, Marta M. Majcherska, Rami Abou Jamra, Ashok Balasubramanyam, Joel B. Krier, Majid Mojarrad, Maria Francesca Bedeschi, Mahshid S. Azamian, Shruti Marwaha, Heather A. Colley, Katrina M. Dipple, Sirisak Chanprasert, Alexa T. McCray, Nicholas Stong, Anne V. Hing, Laura A. Mamounas, Edward C. Smith, Lauren C. Briere, John J.E. Mulvihill, Virginia P. Sybert, Maura R.Z. Ruzhnikov, Valerie Maduro, Frances A. High, Manish J. Butte, Willa Thorson, J. Carl Pallais, Jennefer N. Kohler, Dana Kiley, Raphael Bernier, Christina Lam, Michael J. Bamshad, Patricia A. Ward, Michael F. Wangler, Anita E. Beck, Shinya Yamamoto, Beverly Berg-Rood, Robb Rowley, Gabor T. Marth, Cynthia M. Cooper, Jeffrey G. Jarvik, Thomas C. Markello, Saskia Biskup, Devin Oglesbee, Laura Duncan, Elijah Kravets, Daniel J. Wegner, Mercedes E. Alejandro, Sarah K. Nicholas, Jennifer A. Wambach, Marni J. Falk, Brianna M. Tucker, Marie Morimoto, Corina Heller, Donna Novacic, Camilo Toro, Ashley Andrews, James P. Orengo, Shweta U. Dhar, and Pauline E. Schneeberger
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Death Domain Receptor Signaling Adaptor Proteins ,Programmed cell death ,Developmental Disabilities ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Epidermal growth factor ,medicine ,Guanine Nucleotide Exchange Factors ,Humans ,Death domain ,Kinase ,Original Articles ,Phenotype ,Hypotonia ,Protein Transport ,030104 developmental biology ,Mutation ,Cancer research ,Human medicine ,Neurology (clinical) ,Nervous System Diseases ,Signal transduction ,medicine.symptom ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.
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- 2020
49. Three‐year outcomes of childhood inflammatory bowel disease in New Zealand: A population‐based cohort study
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Natalie G Martin, Amin J Roberts, Helen M. Evans, Jonathan Bishop, and Andrew S. Day
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medicine.medical_specialty ,Crohn's disease ,Hepatology ,treatment ,business.industry ,Gastroenterology ,Pediatric ulcerative colitis ,Original Articles ,Disease ,RC799-869 ,Diseases of the digestive system. Gastroenterology ,medicine.disease ,Inflammatory bowel disease ,Ulcerative colitis ,digestive system diseases ,Disease activity ,Population based cohort ,Internal medicine ,medicine ,Original Article ,business ,Body mass index ,disease activity ,ulcerative colitis - Abstract
Background and Aim High rates of inflammatory bowel disease (IBD) have been documented in New Zealand (NZ) children. The objectives of this study were to describe the outcomes and disease course of childhood IBD in the first 3 years following diagnosis. Methods All children diagnosed with IBD in 2015 in NZ were included. Clinical data obtained during routine care for 3 years following diagnosis were analyzed. Growth parameters, disease activity scores, and blood parameters were compared at diagnosis and follow up. Results Three‐year outcome data were available for 48 of 51 children. At follow up, median age was 15.1 years, and 34 had Crohn's disease (CD), 11 had ulcerative colitis (UC), and three had IBD‐unclassified (IBDU). Although disease progression including development of perianal disease occurred in 13 (38%) of 34 children with CD, the majority (n = 30) had inflammatory disease at follow up. Disease extension occurred in 25% (2/8) of children initially diagnosed with UC. Of all IBD patients, the mean body mass index z‐score increased from −0.40 to +0.10 (P = 0.01). Disease activity scores reduced from diagnosis to follow up in both CD (mean pediatric Crohn's disease activity index 35–6, P, This manuscript aimed, for the first time, to assess and describe the outcomes of a cohort of New Zealand children diagnosed with inflammatory bowel disease. Three years after diagnosis, this group of children was predominantly in remission with satisfactory improvements in growth parameters.
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- 2020
50. Genetic and Environmental Causes of Individual Differences in Borderline Personality Disorder Features and Loneliness are Partially Shared
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Katrina L. Grasby, Ian B. Hickie, Gonneke Willemsen, Lucía Colodro-Conde, Timothy J. Trull, Lannie Ligthart, Julie Aitken Schermer, Nicholas G. Martin, Jane Burns, Dorret I. Boomsma, Biological Psychology, APH - Mental Health, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, and APH - Methodology
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Adult ,Netherlands Twin Register (NTR) ,multivariate genetic modesl ,media_common.quotation_subject ,Individuality ,050109 social psychology ,Health outcomes ,Genetic correlation ,050105 experimental psychology ,Correlation ,medicine ,loneliness ,Personality ,Humans ,0501 psychology and cognitive sciences ,Borderline personality disorder ,Genetics (clinical) ,media_common ,Netherlands ,05 social sciences ,Australia ,Obstetrics and Gynecology ,Loneliness ,twins ,Identity disturbance ,Heritability ,medicine.disease ,genetic correlation ,Pediatrics, Perinatology and Child Health ,multivariate genetic models ,medicine.symptom ,Psychology ,Clinical psychology - Abstract
Loneliness is related to mental and somatic health outcomes, including borderline personality disorder. Here, we analyze the sources of variation that are responsible for the relationship between borderline personality features (including four dimensions, affective instability, identity disturbance, negative relationships, self-harm and a total score) and loneliness. Using genetically informative data from two large nonclinical samples of adult twin pairs from Australia and the Netherlands (N = 11,329), we estimate the phenotypic, genetic and environmental correlations between self-reported borderline personality features and loneliness. Individual differences in borderline personality and loneliness were best explained by additive genetic factors with heritability estimates h2 = 41% for the borderline personality total score and h2 = 36% for loneliness, with the remaining variation explained by environmental influences that were not shared by twins from the same pair. Genetic and environmental factors influencing borderline personality (total score and four subscales separately) were also partial causes of loneliness. The correlation between loneliness and the borderline personality total score was rph = .51. The genetic correlation was estimated at rg = .64 and the environmental correlation at re = .40. Our study suggests common etiological factors in loneliness and borderline personality features.
- Published
- 2020
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