Perceptions of US adolescents and adults with sickle cell disease on their quality of care

Importance: Sickle cell disease (SCD) is the most common inherited red blood cell disorder in the United States, and previous studies have shown that individuals with SCD are affected by multiple health disparities, including stigmatization, inequities in funding, and worse health outcomes, which may preclude their ability to access quality health care. This needs assessment was performed as part of the Sickle Cell Disease Implementation Consortium (SCDIC) to assess barriers to care that may be faced by individuals with SCD. Objective: To assess the SCD-related medical care experience of adolescents and adults with SCD. Design, Setting, and Participants: This one-time survey study evaluated pain interference, quality of health care, and self-efficacy of 440 adults and adolescents (aged 15 to 50 years) with SCD of all genotypes and assessed how these variables were associated with their perceptions of outpatient and emergency department (ED) care. The surveys were administered once during office visits by trained study coordinators at 7 of 8 SCDIC sites in 2018. Results: The SCDIC sites did not report the number of individuals approached to participate in this study; thus, a response rate could not be calculated. In addition, respondents were not required to answer every question in the survey; thus, the response rate per question differed for each variable. Of 440 individuals with SCD, participants were primarily female (245 [55.7%]) and African American (428 [97.3%]) individuals, with a mean (SD) age of 27.8 (8.6) years. The majority of participants (306 of 435 [70.3%]) had hemoglobin SS or hemoglobin S β0-thalassemia. Most respondents (361 of 437 [82.6%]) reported access to nonacute (usual) SCD care, and the majority of respondents (382 of 413 [92.1%]) noted satisfaction with their usual care physician. Of 435 participants, 287 (66.0%) reported requiring an ED visit for acute pain in the previous year. Respondents were less pleased with their ED care than their usual care clinician, with approximately half (146 of 287 [50.9%]) being satisfied with or perceiving having adequate quality care in the ED. Participants also noted that when they experienced severe pain or clinician lack of empathy, this was associated with a negative quality of care. Age group was associated with ED satisfaction, with younger patients (\u3c19 vs 19-30 and 31-50 years) reporting better ED experiences. Conclusions and Relevance: These results suggested that a negative perception of care may be a barrier for patients seeking care. These findings underscore the necessity of implementation studies to improve access to quality care for this population, especially in the acute care setting

Aortic Complications Associated With Pregnancy in Marfan Syndrome: The NHLBI National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139073/1/jah31693.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139073/2/jah31693_am.pd

Human Papillomavirus Detection by Penile Site in Young Men From Kenya

Limited data are available on whether sampling from the penile shaft or urethra increases detection of penile HPV infection in men beyond that found in the glans and coronal sulcus

‘What’s in the NIDDK CDR?’—public query tools for the NIDDK central data repository

The National Institute of Diabetes and Digestive Disease (NIDDK) Central Data Repository (CDR) is a web-enabled resource available to researchers and the general public. The CDR warehouses clinical data and study documentation from NIDDK funded research, including such landmark studies as The Diabetes Control and Complications Trial (DCCT, 1983–93) and the Epidemiology of Diabetes Interventions and Complications (EDIC, 1994–present) follow-up study which has been ongoing for more than 20 years. The CDR also houses data from over 7 million biospecimens representing 2 million subjects. To help users explore the vast amount of data stored in the NIDDK CDR, we developed a suite of search mechanisms called the public query tools (PQTs). Five individual tools are available to search data from multiple perspectives: study search, basic search, ontology search, variable summary and sample by condition. PQT enables users to search for information across studies. Users can search for data such as number of subjects, types of biospecimens and disease outcome variables without prior knowledge of the individual studies. This suite of tools will increase the use and maximize the value of the NIDDK data and biospecimen repositories as important resources for the research community

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). Interpretation: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas

Taking the pulse of Earth's tropical forests using networks of highly distributed plots

Tropical forests are the most diverse and productive ecosystems on Earth. While better understanding of these forests is critical for our collective future, until quite recently efforts to measure and monitor them have been largely disconnected. Networking is essential to discover the answers to questions that transcend borders and the horizons of funding agencies. Here we show how a global community is responding to the challenges of tropical ecosystem research with diverse teams measuring forests tree-by-tree in thousands of long-term plots. We review the major scientific discoveries of this work and show how this process is changing tropical forest science. Our core approach involves linking long-term grassroots initiatives with standardized protocols and data management to generate robust scaled-up results. By connecting tropical researchers and elevating their status, our Social Research Network model recognises the key role of the data originator in scientific discovery. Conceived in 1999 with RAINFOR (South America), our permanent plot networks have been adapted to Africa (AfriTRON) and Southeast Asia (T-FORCES) and widely emulated worldwide. Now these multiple initiatives are integrated via ForestPlots.net cyber-infrastructure, linking colleagues from 54 countries across 24 plot networks. Collectively these are transforming understanding of tropical forests and their biospheric role. Together we have discovered how, where and why forest carbon and biodiversity are responding to climate change, and how they feedback on it. This long-term pan-tropical collaboration has revealed a large long-term carbon sink and its trends, as well as making clear which drivers are most important, which forest processes are affected, where they are changing, what the lags are, and the likely future responses of tropical forests as the climate continues to change. By leveraging a remarkably old technology, plot networks are sparking a very modern revolution in tropical forest science. In the future, humanity can benefit greatly by nurturing the grassroots communities now collectively capable of generating unique, long-term understanding of Earth's most precious forests.Additional co-authors: Susan Laurance, William Laurance, Francoise Yoko Ishida, Andrew Marshall, Catherine Waite, Hannsjoerg Woell, Jean-Francois Bastin, Marijn Bauters, Hans Beeckman, Pfascal Boeckx, Jan Bogaert, Charles De Canniere, Thales de Haulleville, Jean-Louis Doucet, Olivier Hardy, Wannes Hubau, Elizabeth Kearsley, Hans Verbeeck, Jason Vleminckx, Steven W. Brewer, Alfredo Alarcón, Alejandro Araujo-Murakami, Eric Arets, Luzmila Arroyo, Ezequiel Chavez, Todd Fredericksen, René Guillén Villaroel, Gloria Gutierrez Sibauty, Timothy Killeen, Juan Carlos Licona, John Lleigue, Casimiro Mendoza, Samaria Murakami, Alexander Parada Gutierrez, Guido Pardo, Marielos Peña-Claros, Lourens Poorter, Marisol Toledo, Jeanneth Villalobos Cayo, Laura Jessica Viscarra, Vincent Vos, Jorge Ahumada, Everton Almeida, Jarcilene Almeida, Edmar Almeida de Oliveira, Wesley Alves da Cruz, Atila Alves de Oliveira, Fabrício Alvim Carvalho, Flávio Amorim Obermuller, Ana Andrade, Fernanda Antunes Carvalho, Simone Aparecida Vieira, Ana Carla Aquino, Luiz Aragão, Ana Claudia Araújo, Marco Antonio Assis, Jose Ataliba Mantelli Aboin Gomes, Fabrício Baccaro, Plínio Barbosa de Camargo, Paulo Barni, Jorcely Barroso, Luis Carlos Bernacci, Kauane Bordin, Marcelo Brilhante de Medeiros, Igor Broggio, José Luís Camargo, Domingos Cardoso, Maria Antonia Carniello, Andre Luis Casarin Rochelle, Carolina Castilho, Antonio Alberto Jorge Farias Castro, Wendeson Castro, Sabina Cerruto Ribeiro, Flávia Costa, Rodrigo Costa de Oliveira, Italo Coutinho, John Cunha, Lola da Costa, Lucia da Costa Ferreira, Richarlly da Costa Silva, Marta da Graça Zacarias Simbine, Vitor de Andrade Kamimura, Haroldo Cavalcante de Lima, Lia de Oliveira Melo, Luciano de Queiroz, José Romualdo de Sousa Lima, Mário do Espírito Santo, Tomas Domingues, Nayane Cristina dos Santos Prestes, Steffan Eduardo Silva Carneiro, Fernando Elias, Gabriel Eliseu, Thaise Emilio, Camila Laís Farrapo, Letícia Fernandes, Gustavo Ferreira, Joice Ferreira, Leandro Ferreira, Socorro Ferreira, Marcelo Fragomeni Simon, Maria Aparecida Freitas, Queila S. García, Angelo Gilberto Manzatto, Paulo Graça, Frederico Guilherme, Eduardo Hase, Niro Higuchi, Mariana Iguatemy, Reinaldo Imbrozio Barbosa, Margarita Jaramillo, Carlos Joly, Joice Klipel, Iêda Leão do Amaral, Carolina Levis, Antonio S. Lima, Maurício Lima Dan, Aline Lopes, Herison Madeiros, William E. Magnusson, Rubens Manoel dos Santos, Beatriz Marimon, Ben Hur Marimon Junior, Roberta Marotti Martelletti Grillo, Luiz Martinelli, Simone Matias Reis, Salomão Medeiros, Milton Meira-Junior, Thiago Metzker, Paulo Morandi, Natanael Moreira do Nascimento, Magna Moura, Sandra Cristina Müller, Laszlo Nagy, Henrique Nascimento, Marcelo Nascimento, Adriano Nogueira Lima, Raimunda Oliveira de Araújo, Jhonathan Oliveira Silva, Marcelo Pansonato, Gabriel Pavan Sabino, Karla Maria Pedra de Abreu, Pablo José Francisco Pena Rodrigues, Maria Piedade, Domingos Rodrigues, José Roberto Rodrigues Pinto, Carlos Quesada, Eliana Ramos, Rafael Ramos, Priscyla Rodrigues, Thaiane Rodrigues de Sousa, Rafael Salomão, Flávia Santana, Marcos Scaranello, Rodrigo Scarton Bergamin, Juliana Schietti, Jochen Schöngart, Gustavo Schwartz, Natalino Silva, Marcos Silveira, Cristiana Simão Seixas, Marta Simbine, Ana Claudia Souza, Priscila Souza, Rodolfo Souza, Tereza Sposito, Edson Stefani Junior, Julio Daniel do Vale, Ima Célia Guimarães Vieira, Dora Villela, Marcos Vital, Haron Xaud, Katia Zanini, Charles Eugene Zartman, Nur Khalish Hafizhah Ideris, Faizah binti Hj Metali, Kamariah Abu Salim, Muhd Shahruney Saparudin, Rafizah Mat Serudin, Rahayu Sukmaria Sukri, Serge Begne, George Chuyong, Marie Noel Djuikouo, Christelle Gonmadje, Murielle Simo-Droissart, Bonaventure Sonké, Hermann Taedoumg, Lise Zemagho, Sean Thomas, Fidèle Baya, Gustavo Saiz, Javier Silva Espejo, Dexiang Chen, Alan Hamilton, Yide Li, Tushou Luo, Shukui Niu, Han Xu, Zhang Zhou, Esteban Álvarez-Dávila, Juan Carlos Andrés Escobar, Henry Arellano-Peña, Jaime Cabezas Duarte, Jhon Calderón, Lina Maria Corrales Bravo, Borish Cuadrado, Hermes Cuadros, Alvaro Duque, Luisa Fernanda Duque, Sandra Milena Espinosa, Rebeca Franke-Ante, Hernando García, Alejandro Gómez, Roy González-M., Álvaro Idárraga-Piedrahíta, Eliana Jimenez, Rubén Jurado, Wilmar López Oviedo, René López-Camacho, Omar Aurelio Melo Cruz, Irina Mendoza Polo, Edwin Paky, Karen Pérez, Angel Pijachi, Camila Pizano, Adriana Prieto, Laura Ramos, Zorayda Restrepo Correa, James Richardson, Elkin Rodríguez, Gina M. Rodriguez M., Agustín Rudas, Pablo Stevenson, Markéta Chudomelová, Martin Dancak, Radim Hédl, Stanislav Lhota, Martin Svatek, Jacques Mukinzi, Corneille Ewango, Terese Hart, Emmanuel Kasongo Yakusu, Janvier Lisingo, Jean-Remy Makana, Faustin Mbayu, Benjamin Toirambe, John Tshibamba Mukendi, Lars Kvist, Gustav Nebel, Selene Báez, Carlos Céron, Daniel M. Griffith, Juan Ernesto Guevara Andino, David Neill, Walter Palacios, Maria Cristina Peñuela-Mora, Gonzalo Rivas-Torres, Gorky Villa, Sheleme Demissie, Tadesse Gole, Techane Gonfa, Kalle Ruokolainen, Michel Baisie, Fabrice Bénédet, Wemo Betian, Vincent Bezard, Damien Bonal, Jerôme Chave, Vincent Droissart, Sylvie Gourlet-Fleury, Annette Hladik, Nicolas Labrière, Pétrus Naisso, Maxime Réjou-Méchain, Plinio Sist, Lilian Blanc, Benoit Burban, Géraldine Derroire, Aurélie Dourdain, Clement Stahl, Natacha Nssi Bengone, Eric Chezeaux, Fidèle Evouna Ondo, Vincent Medjibe, Vianet Mihindou, Lee White, Heike Culmsee, Cristabel Durán Rangel, Viviana Horna, Florian Wittmann, Stephen Adu-Bredu, Kofi Affum-Baffoe, Ernest Foli, Michael Balinga, Anand Roopsind, James Singh, Raquel Thomas, Roderick Zagt, Indu K. Murthy, Kuswata Kartawinata, Edi Mirmanto, Hari Priyadi, Ismayadi Samsoedin, Terry Sunderland, Ishak Yassir, Francesco Rovero, Barbara Vinceti, Bruno Hérault, Shin-Ichiro Aiba, Kanehiro Kitayama, Armandu Daniels, Darlington Tuagben, John T. Woods, Muhammad Fitriadi, Alexander Karolus, Kho Lip Khoon, Noreen Majalap, Colin Maycock, Reuben Nilus, Sylvester Tan, Almeida Sitoe, Indiana Coronado G., Lucas Ojo, Rafael de Assis, Axel Dalberg Poulsen, Douglas Sheil, Karen Arévalo Pezo, Hans Buttgenbach Verde, Victor Chama Moscoso, Jimmy Cesar Cordova Oroche, Fernando Cornejo Valverde, Massiel Corrales Medina, Nallaret Davila Cardozo, Jano de Rutte Corzo, Jhon del Aguila Pasquel, Gerardo Flores Llampazo, Luis Freitas, Darcy Galiano Cabrera, Roosevelt García Villacorta, Karina Garcia Cabrera, Diego García Soria, Leticia Gatica Saboya, Julio Miguel Grandez Rios, Gabriel Hidalgo Pizango, Eurídice Honorio Coronado, Isau Huamantupa-Chuquimaco, Walter Huaraca Huasco, Yuri Tomas Huillca Aedo, Jose Luis Marcelo Peña, Abel Monteagudo Mendoza, Vanesa Moreano Rodriguez, Percy Núñez Vargas, Sonia Cesarina Palacios Ramos, Nadir Pallqui Camacho, Antonio Peña Cruz, Freddy Ramirez Arevalo, José Reyna Huaymacari, Carlos Reynel Rodriguez, Marcos Antonio Ríos Paredes, Lily Rodriguez Bayona, Rocio del Pilar Rojas Gonzales, Maria Elena Rojas Peña, Norma Salinas Revilla, Yahn Carlos Soto Shareva, Raul Tupayachi Trujillo, Luis Valenzuela Gamarra, Rodolfo Vasquez Martinez, Jim Vega Arenas, Christian Amani, Suspense Averti Ifo, Yannick Bocko, Patrick Boundja, Romeo Ekoungoulou, Mireille Hockemba, Donatien Nzala, Alusine Fofanah, David Taylor, Guillermo Bañares-de Dios, Luis Cayuela, Íñigo Granzow-de la Cerda, Manuel Macía, Juliana Stropp, Maureen Playfair, Verginia Wortel, Toby Gardner, Robert Muscarella, Hari Priyadi, Ervan Rutishauser, Kuo-Jung Chao, Pantaleo Munishi, Olaf Bánki, Frans Bongers, Rene Boot, Gabriella Fredriksson, Jan Reitsma, Hans ter Steege, Tinde van Andel, Peter van de Meer, Peter van der Hout, Mark van Nieuwstadt, Bert van Ulft, Elmar Veenendaal, Ronald Vernimmen, Pieter Zuidema, Joeri Zwerts, Perpetra Akite, Robert Bitariho, Colin Chapman, Eilu Gerald, Miguel Leal, Patrick Mucunguzi, Miguel Alexiades, Timothy R. Baker, Karina Banda, Lindsay Banin, Jos Barlow, Amy Bennett, Erika Berenguer, Nicholas Berry, Neil M. Bird, George A. Blackburn, Francis Brearley, Roel Brienen, David Burslem, Lidiany Carvalho, Percival Cho, Fernanda Coelho, Murray Collins, David Coomes, Aida Cuni-Sanchez, Greta Dargie, Kyle Dexter, Mat Disney, Freddie Draper, Muying Duan, Adriane Esquivel-Muelbert, Robert Ewers, Belen Fadrique, Sophie Fauset, Ted R. Feldpausch, Filipe França, David Galbraith, Martin Gilpin, Emanuel Gloor, John Grace, Keith Hamer, David Harris, Tommaso Jucker, Michelle Kalamandeen, Bente Klitgaard, Aurora Levesley, Simon L. Lewis, Jeremy Lindsell, Gabriela Lopez-Gonzalez, Jon Lovett, Yadvinder Malhi, Toby Marthews, Emma McIntosh, Karina Melgaço, William Milliken, Edward Mitchard, Peter Moonlight, Sam Moore, Alexandra Morel, Julie Peacock, Kelvin Peh, Colin Pendry, R. Toby Pennington, Luciana de Oliveira Pereira, Carlos Peres, Oliver L. Phillips, Georgia Pickavance, Thomas Pugh, Lan Qie, Terhi Riutta, Katherine Roucoux, Casey Ryan, Tiina Sarkinen, Camila Silva Valeria, Dominick Spracklen, Suzanne Stas, Martin Sullivan, Michael Swaine, Joey Talbot, James Taplin, Geertje van der Heijden, Laura Vedovato, Simon Willcock, Mathew Williams, Luciana Alves, Patricia Alvarez Loayza, Gabriel Arellano, Cheryl Asa, Peter Ashton, Gregory Asner, Terry Brncic, Foster Brown, Robyn Burnham, Connie Clark, James Comiskey, Gabriel Damasco, Stuart Davies, Tony Di Fiore, Terry Erwin, William Farfan-Rios, Jefferson Hall, David Kenfack, Thomas Lovejoy, Roberta Martin, Olga Martha Montiel, John Pipoly, Nigel Pitman, John Poulsen, Richard Primack, Miles Silman, Marc Steininger, Varun Swamy, John Terborgh, Duncan Thomas, Peter Umunay, Maria Uriarte, Emilio Vilanova Torre, Ophelia Wang, Kenneth Young, Gerardo A. Aymard C., Lionel Hernández, Rafael Herrera Fernández, Hirma Ramírez-Angulo, Pedro Salcedo, Elio Sanoja, Julio Serrano, Armando Torres-Lezama, Tinh Cong Le, Trai Trong Le, Hieu Dang Tra

Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation.

Oxygen-dependent proteolytic destruction of hypoxia-inducible factor-alpha (HIF-alpha) subunits plays a central role in regulating transcriptional responses to hypoxia. Recent studies have defined a key function for the von Hippel-Lindau tumour suppressor E3 ubiquitin ligase (VHLE3) in this process, and have defined an interaction with HIF-1 alpha that is regulated by prolyl hydroxylation. Here we show that two independent regions within the HIF-alpha oxygen-dependent degradation domain (ODDD) are targeted for ubiquitylation by VHLE3 in a manner dependent upon prolyl hydroxylation. In a series of in vitro and in vivo assays, we demonstrate the independent and non-redundant operation of each site in regulation of the HIF system. Both sites contain a common core motif, but differ both in overall sequence and in the conditions under which they bind to the VHLE3 ligase complex. The definition of two independent destruction domains implicates a more complex system of pVHL-HIF-alpha interactions, but reinforces the role of prolyl hydroxylation as an oxygen-dependent destruction signal

Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation

Oxygen-dependent proteolytic destruction of hypoxia-inducible factor-α (HIF-α) subunits plays a central role in regulating transcriptional responses to hypoxia. Recent studies have defined a key function for the von Hippel–Lindau tumour suppressor E3 ubiquitin ligase (VHLE3) in this process, and have defined an interaction with HIF-1α that is regulated by prolyl hydroxylation. Here we show that two independent regions within the HIF-α oxygen-dependent degradation domain (ODDD) are targeted for ubiquitylation by VHLE3 in a manner dependent upon prolyl hydroxylation. In a series of in vitro and in vivo assays, we demonstrate the independent and non-redundant operation of each site in regulation of the HIF system. Both sites contain a common core motif, but differ both in overall sequence and in the conditions under which they bind to the VHLE3 ligase complex. The definition of two independent destruction domains implicates a more complex system of pVHL–HIF-α interactions, but reinforces the role of prolyl hydroxylation as an oxygen-dependent destruction signal