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1. Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism

Author

Bruna Pilan, Ana Claudia Latronico, Antonio Lerario, Anna Flavia Figueredo Benedetti, Victor Srougi, Luciano F. Drager, Leticia A P Vilela, Tatiana S Goldbaum, Luiz Aparecido Bortolotto, Berenice B. Mendonca, Marcela Rassi-Cruz, Maria Adelaide Albergaria Pereira, Fabio R. Faucz, Lucas Santos de Santana, Aline C B S Cavalcante, Fabio Y Tanno, Jose Luis Chambo, Andrea Gutierrez Maria, Maria Candida Barisson Villares Fragoso, Francisco Cesar Carnevale, Maria Claudia Nogueira Zerbini, Edra London, Madson Q. Almeida, and Constantine A. Stratakis

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Article, Germline, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Primary aldosteronism, Internal medicine, Hyperaldosteronism, medicine, Humans, Gene, Aged, Messenger RNA, business.industry, Phosphodiesterase, Transfection, Middle Aged, Hyperplasia, medicine.disease, Cyclic Nucleotide Phosphodiesterases, Type 2, Cyclic Nucleotide Phosphodiesterases, Type 3, 030104 developmental biology, medicine.anatomical_structure, Oncology, Zona glomerulosa, 030220 oncology & carcinogenesis, Female, business
Abstract

Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, ‘sporadic’ bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of genetic etiologies of PA.

Published
2021

2. Mass spectrometry-based steroid profiling in primary bilateral macronodular adrenocortical hyperplasia

Author

Martin Reincke, Jérôme Bertherat, Fabio R. Faucz, Graeme Eisenhofer, Fady Hannah-Shmouni, Anna Vaczlavik, Mirko Peitzsch, Andrea Gutierrez Maria, Annabel Berthon, Andrew P. Demidowich, Jimmy Masjkur, Fideline Bonnet-Serrano, Constantine A. Stratakis, and Juan Medina Briceno

Subjects
Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Adrenal Gland Neoplasms, Article, Germline, Steroid, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Tandem Mass Spectrometry, Corticosterone, Internal medicine, medicine, Humans, Cushing Syndrome, Adrenocortical hyperplasia, Aldosterone, business.industry, Middle Aged, Cross-Sectional Studies, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Female, Steroids, business
Abstract

Biochemical characterization of primary bilateral macronodular adrenocortical hyperplasia (PBMAH) by distinct plasma steroid profiles and its putative correlation to disease has not been previously studied. LC-MS/MS–based steroid profiling of 16 plasma steroids was applied to 36 subjects (22 females, 14 males) with PBMAH, 19 subjects (16 females, 3 males) with other forms of adrenal Cushing's syndrome (ACS), and an age and sex-matched control group. Germline ARMC5 sequencing was performed in all PBMAH cases. Compared to controls, PBMAH showed increased plasma 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, 18-hydroxycortisol, and aldosterone, but lower progesterone, DHEA, and DHEA-S with distinct differences in subjects with and without pathogenic variants in ARMC5. Steroids that showed isolated differences included cortisol and 18-oxocortisol with higher (P ARMC5 was achieved in 91.7% of subjects with PBMAH. Subjects with PBMAH show distinctive plasma steroid profiles that may offer a supplementary single-test alternative for screening purposes.

Published
2020

3. Cushing Syndrome in a Pediatric Patient With a KCNJ5 Variant and Successful Treatment With Low-dose Ketoconazole

Author

Meg Keil, Cole Malloy, Constantine A. Stratakis, Andrea Gutierrez Maria, Christina Tatsi, Lin Lin, Nick Settas, Fady Hannah-Shmouni, Dax A. Hoffman, Edra London, and Chelsi Flippo

Subjects
0301 basic medicine, medicine.medical_specialty, Familial hyperaldosteronism, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Mutation, Missense, 030209 endocrinology & metabolism, Context (language use), Biochemistry, 03 medical and health sciences, Cushing syndrome, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Internal medicine, KCNJ5, Medicine, Humans, Child, PRKAR1A, Cushing Syndrome, Clinical Research Articles, Cells, Cultured, Aldosterone, biology, Dose-Response Relationship, Drug, business.industry, Biochemistry (medical), medicine.disease, Hyperaldosteronism, United States, PRKACA, 030104 developmental biology, HEK293 Cells, Ketoconazole, Treatment Outcome, chemistry, G Protein-Coupled Inwardly-Rectifying Potassium Channels, biology.protein, Female, business
Abstract

Context Pathogenic variants in KCNJ5, encoding the GIRK4 (Kir3.4) potassium channel, have been implicated in the pathogenesis of familial hyperaldosteronism type-III (FH-III) and sporadic primary aldosteronism (PA). In addition to aldosterone, glucocorticoids are often found elevated in PA in association with KCNJ5 pathogenic variants, albeit at subclinical levels. However, to date no GIRK4 defects have been linked to Cushing syndrome (CS). Patient We present the case of a 10-year-old child who presented with CS at an early age due to bilateral adrenocortical hyperplasia (BAH). The patient was placed on low-dose ketoconazole (KZL), which controlled hypercortisolemia and CS-related signs. Discontinuation of KZL for even 6 weeks led to recurrent CS. Results Screening for known genes causing cortisol-producing BAHs (PRKAR1A, PRKACA, PRKACB, PDE11A, PDE8B, ARMC5) failed to identify any gene defects. Whole-exome sequencing showed a novel KCNJ5 pathogenic variant (c.506T>C, p.L169S) inherited from her father. In vitro studies showed that the p.L169S variant affects conductance of the Kir3.4 channel without affecting its expression or membrane localization. Although there were no effects on steroidogenesis in vitro, there were modest changes in protein kinase A activity. In silico analysis of the mutant channel proposed mechanisms for the altered conductance. Conclusion We present a pediatric patient with CS due to BAH and a germline defect in KCNJ5. Molecular investigations of this KCNJ5 variant failed to show a definite cause of her CS. However, this KCNJ5 variant differed in its function from KCNJ5 defects leading to PA. We speculate that GIRK4 (Kir3.4) may play a role in early human adrenocortical development and zonation and participate in the pathogenesis of pediatric BAH.

Published
2021

4. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19 : a meta-analysis

Author

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, [missing], Domingo, Pere, Mur, Isabel, Mateo, Gracia María, Gutierrez, Maria del Mar, Pomar, Virginia, de Benito, Natividad, Corbacho, Noemí, Herrera, Silvia, Millan, Lucia, Muñoz, Jessica, Malouf, Jorge, Molas, Maria Ema, Asensi, Victor, Horcajada, Juan Pablo, Estrada, Vicente, Gutierrez, Felix, Torres, Ferran, Perez-Molina, Jose A, Fortun, Jesús, Villar, Luisa M, Hohenthal, Ulla, Marttila, Harri, Vuorinen, Tytti, Nordberg, Marika, Valtonen, Mika, Frigault, Matthew J, Mansour, Michael K, Patel, Naomi J, Fernandes, Ana, Harvey, Liam, Foulkes, Andrea S, Healy, Brian C, Shah, Ruta, Bensaci, Ana Maria, Woolley, Ann E., Nikiforow, Sarah, Lin, Nina, Sagar, Manish, Shrager, Harry, Huckins, David S., Axelrod, Matthew, Pincus, Michael D, Fleisher, Jorge, Lampa, Jon, Nowak, Piotr, Vesterbacka, Jan C., Rasmuson, Johan, Skorup, Paul, Janols, Helena, Niward, Katarina F, Chatzidionysiou, Katerina, Asgeirsson, Hilmir, Parke, Åsa, Blennow, Ola, Svensson, Anna-Karin, Aleman, Soo, Sönnerborg, Anders, Henter, Jan-Inge, Horne, Anna Carin, Al-Beidh, Farah, Angus, Derek, Annane, Djillali, Arabi, Yaseen, Beane, Abigail, Berry, Scott, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Buxton, Meredith, Cheng, Allen, Cove, Matt, De Jong, Menno, Derde, Lennie, Estcourt, Lise, Goossens, Herman, Gordon, Anthony, Green, Cameron, Haniffa, Rashan, Ichihara, Nao, Lamontagne, Francois, Lawler, Patrick, Litton, Ed, Marshall, John, McArthur, Colin, McAuley, Daniel, McGuinness, Shay, McVerry, Bryan, Montgommery, Stephanie, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, Parke, Rachael, Parker, Jane, Reyes, Felipe, Rowan, Kathryn, Saito, Hiroki, Santos, Marlene, Seymour, Chris, Shankar-Hari, Manu, Turgeon, Alexis, Turner, Anne, van Bentum-Puijk, Wilma, van de Veerdonk, Frank, Webb, Steve, Zarychanski, Ryan, Baillie, J Kenneth, Beasley, Richard, Cooper, Nichola, Fowler, Robert, Galea, James, Hills, Thomas, King, Andrew, Morpeth, Susan, Netea, Mihai, Ogungbenro, Kayode, Pettila, Ville, Tong, Steve, Uyeki, Tim, Youngstein, Taryn, Higgins, Alisa, Lorenzi, Elizabeth, Berry, Lindsay, Salama, Carlos, Rosas, Ivan O., Ruiz-Antorán, Belén, Muñez Rubio, Elena, Ramos Martínez, Antonio, Campos Esteban, José, Avendaño Solá, Cristina, Pizov, Reuven, Sanz Sanz, Jesus, Abad-Santos, Francisco, Bautista-Hernández, Azucena, García-Fraile, Lucio, Barrios, Ana, Gutiérrez Liarte, Ángela, Alonso Pérez, Tamara, Rodríguez-García, Sebastian C, Mejía-Abril, Gina, Prieto, Jose Carlos, Leon, Rafael, VEIGA, VIVIANE C., SCHEINBERG, PHILLIP, FARIAS, DANIELLE L.C., PRATS, JOÃO G., CAVALCANTI, ALEXANDRE B., MACHADO, FLAVIA R., ROSA, REGIS G., BERWANGER, OTÁVIO, AZEVEDO, LUCIANO C.P., LOPES, RENATO D., DOURADO, LETICIA K., CASTRO, CLAUDIO G., ZAMPIERI, FERNANDO G., AVEZUM, ALVARO, LISBOA, THIAGO C., ROJAS, SALOMÓN S.O., COELHO, JULIANA C., LEITE, RODRIGO T., CARVALHO, JULIO CESAR, ANDRADE, LUIS E.C., SANDES, ALEX R., PINTÃO, MARIA CAROLINA T., SANTOS, SUELI V., ALMEIDA, THIAGO M.L., COSTA, ANDRÉ N., GEBARA, OTAVIO C.E., FREITAS, FLAVIO G.R., PACHECO, EDUARDO S., MACHADO, DAVID J.B., MARTIN, JOSIANE, CONCEIÇÃO, FABIO G., SIQUEIRA, SUELLEN R.R., DAMIANI, LUCAS P., ISHIHARA, LUCIANA M., SCHNEIDER, DANIEL, DE SOUZA, DENISE, Hermine, Olivier, Mariette, Xavier, Tharaux, Pierre Louis, Resche Rigon, Matthieu, Porcher, Raphael, Ravaud, Philippe, Azoulay, Elie, Cadranel, Jacques, Emmerich, Joseph, Fartoukh, Muriel, Guidet, Bertrand, Humbert, Marc, Lacombe, Karine, Mahevas, Matthieu, Pene, Frédéric, Pourchet-Martinez, Valérie, Schlemmer, Frédéric, Tibi, Annick, Yazdanpanah, Yazdan, Dougados, Maxime, Bureau, Serge, Horby, Peter W, Landray, Martin J, Baillie, Kenneth J, Buch, Maya H, Chappell, Lucy C, Day, Jeremy N, Faust, Saul N, Haynes, Richard, Jaki, Thomas, Jeffery, Katie, Juszczak, Edmund, Lim, Wei Shen, Mafham, Marion, Montgomery, Alan, Mumford, Andrew, Thwaites, Guy, Kamarulzaman, Adeeba, Syed Omar, Sharifah Faridah, Ponnampalavanar, Sasheela, Raja Azwa, Raja Iskandar Syah, Wong, Pui Li, Kukreja, Anjanna, Ong, Hang Cheng, Sulaiman, Helmi, Basri, Sazali, Ng, Rong Xiang, Megat Johari, Bushra, Rajasuriar, Reena, Chong, Meng Li, Neelamegam, Malinee, Syed Mansor, Syed Mukhtar, Zulhaimi, Nurul Syuhada, Lee, Cheng Siang, Altice, Frederick, Price, Christina, Malinis, Maricar, Hasan, Mohd Shahnaz, Wong, Chee Kuan, Chidambaram, Suresh, Misnan, Nor Arisah, Mohd Thabit, Alif Adlan, Sim, Benedict, Bidin, Farah Nadiah, Mohd Abd Rahim, Mohd Abd Hafiz, Saravanamuttu, Sujana, Tuang, Wei Xuan, Mohamed Gani, Yasmin, Thangavelu, Suvintheran, Tay, Kim Heng, Ibrahim, Nur Munirah, Halid, Luqman Alhakim, Tan, Kok Tong, Mukri, Mohd Noor Azreet, Arip, Masita, Koh, Hui Moon, Syed Badaruddin, Syarifah Nurul Ain, Raja Sureja, Letchumi, Chun, Geok Ying, TORRE-CISNEROS, JULIAN, MERCHANTE, NICOLAS, LEON, RAFAEL, CARCEL, SHEILA, GARRIDO, JOSE CARLOS, Galun, Eitan, Soriano, Alex, Martínez, José Antonio, Castán, Clara, Paredes, Roger, Dalmau, David, Carbonell, Cristina, Espinosa, Gerard, Castro, Pedro, Muñóz, José, Almuedo, Alex, Prieto, Sergio, Pacheco, Iván, Ratain, Mark, Pisano, Jennifer, Strek, Mary, Adegunsoye, Ayodeji, Karrison, Theodore, Declercq, Jozefien, Van Damme, Karel, De Leeuw, Elisabeth, Bosteels, Cedric, Maes, Bastiaan, Vale, Claire L., Godolphin, Peter J., Fisher, David, Higgins, Julian P. T., Spiga, Francesca, Savovic, Jelena, Tierney, Jayne, Baron, Gabriel, Benbenishty, Julie S., Berry, Lindsay R., Broman, Niklas, Cavalcanti, Alexandre Biasi, Colman, Roos, De Buyser, Stefanie, Derde, Lennie P. G., Omar, Sharifah Faridah, Fernandez-Cruz, Ana, Feuth, Thijs, Garcia, Felipe, Garcia-Vicuna, Rosario, Gonzalez-Alvaro, Isidoro, Gordon, Anthony C., Horby, Peter W., Horick, Nora K., Kumar, Kuldeep, Lambrecht, Bart, Landray, Martin J., Leal, Lorna, Lederer, David J., Merchante, Nicolas, Mohan, Shalini V., Nivens, Michael C., Oksi, Jarmo, Perez-Molina, Jose A., Postma, Simone, Ramanan, Athimalaipet V., Reid, Pankti D., Rutgers, Abraham, Sancho-Lopez, Aranzazu, Seto, Todd B., Sivapalasingam, Sumathi, Soin, Arvinder Singh, Staplin, Natalie, Stone, John H., Strohbehn, Garth W., Sunden-Cullberg, Jonas, Torre-Cisneros, Julian, Tsai, Larry W., van Hoogstraten, Hubert, van Meerten, Tom, Veiga, Viviane Cordeiro, Westerweel, Peter E., Diaz, Janet V., Marshall, John C., Sterne, Jonathan A. C., Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), World Health Organization, and Group, WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working

Subjects
Male, medicine.medical_specialty, Randomization, Secondary infection, Placebo, Antibodies, Monoclonal, Humanized, Internal medicine, Cause of Death, Medicine and Health Sciences, Medicine, Humans, Prospective Studies, Prospective cohort study, Glucocorticoids, METAANALYSIS, Cause of death, Aged, Randomized Controlled Trials as Topic, business.industry, Coinfection, Interleukin-6, COVID-19, Odds ratio, General Medicine, Middle Aged, Respiration, Artificial, COVID-19 Drug Treatment, Clinical trial, Hospitalization, Meta-analysis, Disease Progression, Drug Therapy, Combination, Female, business
Abstract

[Importance] Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm., [Objective] To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes., [Data Sources] Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts., [Study Selection] Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria., [Data Extraction and Synthesis] In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance–weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality., [Main Outcomes and Measures] The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days., [Results] A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P, [Conclusions and Relevance] In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality., [Trial Registration] PROSPERO Identifier: CRD42021230155., Funding for administrative and communications support was provided by the World Health Organization.

Published
2021

5. Predictores de eventos clínicos en una cohorte de pacientes con enfermedad de Fabry en tratamiento sustitutivo enzimático

Author

Goicoechea, Marian, Gomez Preciado, Francisco, Benito, Silvia, Torras Ambròs, Joan, Torra, Roser, Huerta, Ana, Restrepo, Alejandra, Ugalde, Jessica, Astudillo, Daniela Estefania, Agraz, Irene, Lopez Mendoza, Manuel, Arriba, Gabriel de, Corchete, Elena, Quiroga, Borja, Gutierrez, Maria Jose, Martin Conde, Maria Luisa, Lopes, Vanessa, Ramos, Carmela, Mendez, Irene, Cao, Mercedes, Dominguez, Fernando, Ortiz, Alberto, Spanish Group for the Study of Glomerular Diseases (GLOSEN), Spanish Group for the Study of Glomerular Diseases (GLOSEN), Institut Català de la Salut, [Goicoechea M] Servicio de Nefrología Hospital General Universitario Gregorio Marañon, Spain. Red de Investigación Renal (REDinRen), Fondos FEDER, Spain. [Gomez-Preciado F] Servicio de Nefrología Hospital Universitario de Bellvitge, Spain. [Benito S] Servicio de Nefrología Fundacion Puigvert, Spain. [Torras J] Red de Investigación Renal (REDinRen), Fondos FEDER, Spain. Servicio de Nefrología Hospital Universitario de Bellvitge, Spain. [Torra R] Red de Investigación Renal (REDinRen), Fondos FEDER, Spain. Servicio de Nefrología Fundacion Puigvert, Spain. [Huerta A] Servicio de Nefrología Hospital Universitario Puerta del Hierro Majadahonda, Spain. [Agraz I] Servei de Nefrologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
0301 basic medicine, Male, Fabry's disease, 030232 urology & nephrology, 030105 genetics & heredity, chemistry.chemical_compound, 0302 clinical medicine, Clinical trials, Chronic kidney disease, Medicine, terapéutica::farmacoterapia::terapia enzimática::tratamiento de sustitución enzimática [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Tratamiento enzimático sustitutivo, Otros calificadores::/terapia [Otros calificadores], Kidney diseases, Renal events, Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Cerebrovascular Disorders::Cerebral Small Vessel Diseases::Fabry Disease [DISEASES], Incidence (epidemiology), Enfermedad de Fabry, Enzyme replacement therapy, Middle Aged, Enzymes, Nephrology, Creatinine, Cohort, Female, Adult, medicine.medical_specialty, Eventos renales, enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades cerebrales metabólicas::enfermedades cerebrales metabólicas congénitas::enfermedades por almacenamiento lisosómico del sistema nervioso::esfingolipidosis::enfermedad de Fabry [ENFERMEDADES], 03 medical and health sciences, Malaltia de Fabry, Internal medicine, Albumins, Humans, Enzyme Replacement Therapy, Renal Insufficiency, Chronic, Enfermedad renal crónica, Retrospective Studies, Fabry disease, business.industry, Proportional hazards model, Enzims - Ús terapèutic, diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Other subheadings::/therapy [Other subheadings], medicine.disease, Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Diseases of the genitourinary system. Urology, Log-rank test, chemistry, Avaluació de resultats (Assistència sanitària), Malalties del ronyó, Fabry Disease, RC870-923, Enzims, business, Ronyons - Malalties - Tractament, Therapeutics::Drug Therapy::Enzyme Therapy::Enzyme Replacement Therapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Kidney disease, Assaigs clínics
Abstract

Enfermedad de Fabry; Enfermedad renal crónica; Tratamiento enzimático sustitutivo Fabry disease; Chronic kidney disease; Enzyme replacement therapy Malaltia de Fabry; Malaltia renal crònica; Tractament enzimàtic substitutiu Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT. Study design: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). Results: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242-128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models. Conclusions: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes. El objetivo de este estudio es realizar un mapa del tratamiento actual de la enfermedad de Fabry en España, analizando el efecto de diferentes factores en el desarrollo de eventos clínicos a largo plazo. Diseño del estudio: Análisis observacional retrospectivo multicéntrico. Criterios de inclusión: pacientes diagnosticados y tratados de enfermedad de Fabry. Se recogieron datos generales en relación con el diagnóstico, síntomas y tipo mutación, tipo de tratamiento recibido, evolución renal y cardiológica. Durante un tiempo de seguimiento de 60 meses (24-120), se recogió el primer evento clínico tras el inicio de tratamiento sustitutivo enzimático definido como mortalidad, evento renal, cardiológico o neurológico. Resultados: Se incluyeron 69 pacientes (42 H, 27 M) con una edad media de 44,6 ± 13,7 años. A los cinco años de tratamiento, el FGe y la hipertrofia ventricular izquierda se mantuvieron estables, y la albuminuria tiende a disminuir, siendo este descenso más significativo en el grupo de pacientes tratados con beta-galactosidasa (de 242 a 128mg/g (p = 0,05). Veintiún pacientes sufrieron un evento clínico (30%): seis renales, dos neurológicos y 13 cardiológicos (incluidas tres muertes). Los pacientes con ERC (FGe < 60) antes del inicio de tratamiento tuvieron más eventos (log-rank 12.423, p = 0,001), manteniéndose la predicción si excluíamos los eventos renales (log-rank 4.086 (p = 0,043) en hombres y mujeres. La peor función renal al inicio del tratamiento aumentó entre tres y siete veces el riesgo de eventos clínicos en diferentes modelos de Cox ajustados. Conclusiones: La función renal al inicio de tratamiento sustitutivo enzimático es la principal predictora de desarrollo de eventos clínicos a largo plazo, tanto en hombres como mujeres. El inicio de tratamiento sustitutivo enzimático precoz antes del desarrollo de ERC mejoraría el pronóstico. MG, JT, AO, RT are supported by ISCIII RETIC REDINREN, RD016/009 and FEDER funds

Published
2021

6. Volumetric Modeling of Adrenal Gland Size in Primary Bilateral Macronodular Adrenocortical Hyperplasia

Author

Andrea Gutierrez Maria, Crystal Kamilaris, Georgios Z. Papadakis, Andrew P. Demidowich, Naris Nilubol, Amit Tirosh, Graeme Eisenhofer, Fady Hannah-Shmouni, Mihail Zilbermint, Martin Reincke, Fabio R. Faucz, Rachel Wurth, Leah T. Braun, Annabel Berthon, Jancarlos Camacho, Ahmed Hamimi, Ahmed M. Gharib, and Constantine A. Stratakis

Subjects
0301 basic medicine, medicine.medical_specialty, Adrenal gland, business.industry, Endocrinology, Diabetes and Metabolism, Radiography, Urology, 030209 endocrinology & metabolism, Context (language use), medicine.disease, 03 medical and health sciences, Cushing syndrome, 030104 developmental biology, 0302 clinical medicine, Clinical research, Primary aldosteronism, medicine.anatomical_structure, Cohort, medicine, business, Adrenocortical hyperplasia, Clinical Research Articles
Abstract

Context Radiological characterization of adrenal size in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) has not been previously investigated. Objective We hypothesized that volumetric modeling of adrenal gland size may correlate with biochemical disease severity in patients with PBMAH. Secondary analysis of patients with concurrent primary aldosteronism (PA) was performed. Design A retrospective cross-sectional analysis of 44 patients with PBMAH was conducted from 2000 to 2019. Setting Tertiary care clinical research center. Patients Patients were diagnosed with PBMAH based upon clinical, genetic, radiographic and biochemical characteristics. Intervention Clinical, biochemical, and genetic data were obtained. Computed tomography scans were used to create volumetric models by manually contouring both adrenal glands in each slice using Vitrea Core Fx v6.3 software (Vital Images, Minnetonka, Minnesota). Main Outcome and Measures 17-hydroxycorticosteroids (17-OHS), ARMC5 genetics, and aldosterone-to-renin ratio (ARR) were retrospectively obtained. Pearson test was used for correlation analysis of biochemical data with adrenal volume. Results A cohort of 44 patients with PBMAH was evaluated, with a mean age (±SD) of 53 ± 11.53. Eight patients met the diagnostic criteria for PA, of whom 6 (75%) were Black. In the Black cohort, total adrenal volumes positively correlated with midnight cortisol (R = 0.76, P = 0.028), urinary free cortisol (R = 0.70, P = 0.035), and 17-OHS (R = 0.87, P = 0.0045), with a more pronounced correlation with left adrenal volume alone. 17-OHS concentration positively correlated with total, left, and right adrenal volume in patients harboring pathogenic variants in ARMC5 (R = 0.72, P = 0.018; R = 0.65, P = 0.042; and R = 0.73, P = 0.016, respectively). Conclusions Volumetric modeling of adrenal gland size may associate with biochemical severity in patients with PBMAH, with particular utility in Black patients.

Published
2020

7. ARMC5 Alterations in Patients With Sporadic Neuroendocrine Tumors and Multiple Endocrine Neoplasia Type 1 (MEN1)

Author

Dusko Dundjerovic, Andrea Gutierrez Maria, Jadranka Antic, Constantine A. Stratakis, Ivana Milicevic, Fabio R. Faucz, Bojana B. Beleslin-Cokic, Gordana Rodic, Bojana Ilic, Annabel Berthon, Valentina I Elezovic-Kovacevic, and Svetozar Damjanovic

Subjects
0301 basic medicine, Male, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, DNA Mutational Analysis, Adrenal Gland Neoplasms, Loss of Heterozygosity, 030105 genetics & heredity, Neuroendocrine tumors, Biochemistry, Germline, Loss of heterozygosity, Cohort Studies, Endocrinology, Multiple endocrine neoplasia, Child, Middle Aged, Neuroendocrine Tumors, Parathyroid Neoplasms, Immunohistochemistry, Female, Haploinsufficiency, Adenoma, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, endocrine system, Adolescent, Context (language use), Paraganglioma, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Multiple Endocrine Neoplasia Type 1, Humans, MEN1, Pituitary Neoplasms, Thyroid Neoplasms, Online Only Articles, Germ-Line Mutation, Aged, Armadillo Domain Proteins, business.industry, Biochemistry (medical), Sequence Analysis, DNA, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Cancer research, business
Abstract

Context Adrenal lesions are frequent among patients with sporadic neuroendocrine tumors (spNETs) or multiple endocrine neoplasia type 1 (MEN1). Armadillo repeat-containing 5 (ARMC5)-inactivating variants cause adrenal tumors and possibly other neoplasms. Objective The objective of this work is to investigate a large cohort spNETs or MEN1 patients for changes in the ARMC5 gene. Patients and Methods A total of 111 patients, 94 with spNET and 17 with MEN1, were screened for ARMC5 germline alterations. Thirty-six tumors (18 spNETs and 18 MEN1 related) were collected from 20 patients. Blood and tumor DNA samples were genotyped using Sanger sequencing and microsatellite markers for chromosomes. ARMC5 and MEN1 expression were assessed by immunohistochemistry. Results In 76 of 111 (68.4%) patients, we identified 16 different ARMC5 germline variants, 2 predicted as damaging. There were no differences in the prevalence of ARMC5 variants depending on the presence of MEN1-related adrenal lesions. Loss of heterozygosity (LOH) at chromosome 16p and ARMC5 germline variants were present together in 23 or 34 (67.6%) tumors; in 7 of 23 (30.4%) their presence led to biallelic inactivation of the ARMC5 gene. The latter was more prevalent in MEN1-related tumors than in spNETs (88.9% vs 38.9%; P = .005). LOH at the chromosome 16p (ARMC5) and 11q (MEN1) loci coexisted in 16/18 MEN1-related tumors, which also expressed lower ARMC5 (P = .02) and MEN1 (P = .01) proteins compared to peritumorous tissues. Conclusion Germline ARMC5 variants are common among spNET and MEN1 patients. ARMC5 haploinsufficiency or biallelic inactivation in spNETs and MEN1-related tumors suggests that ARMC5 may have a role in modifying the phenotype of patients with spNETs and/or MEN1 beyond its known role in macronodular adrenocortical hyperplasia.

Published
2020

8. Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study

Author

Tedesco-Silva, Helio, Pascual, Julio, Viklicky, Ondrej, Bašić-Jukić, Nikolina, Cassuto, Elisabeth, Kim, Dean Y., Cruzado, Josep M., Sommerer, Claudia, Adel Bakr, Mohamed, Garcia, Valter D., Uyen, Huynh-Do, Russ, Graeme, Soo Kim, Myoung, Kuypers, Dirk, Buchler, Matthias, Citterio, Franco, Hernandez Gutierrez, Maria Pilar, Bernhardt, Peter, Chadban, Steve, and Rački, Sanjin

Subjects
Adult, Graft Rejection, medicine.medical_specialty, Time Factors, Settore MED/18 - CHIRURGIA GENERALE, Calcineurin Inhibitors, Urology, 030230 surgery, Kidney transplant, Tacrolimus, law.invention, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, Randomized controlled trial, law, Risk Factors, Medicine, Humans, Everolimus, 610 Medicine & health, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Internal Medicine, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Interna medicina, Transplantation, Kidney, business.industry, Graft Survival, Middle Aged, Mycophenolic Acid, Kidney Transplantation, Calcineurin, medicine.anatomical_structure, Treatment Outcome, Multicenter study, Cyclosporine, 030211 gastroenterology & hepatology, everolimus, kidney transplantation, Drug Therapy, Combination, business, Standard therapy, Immunosuppressive Agents, medicine.drug
Abstract

Background. The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail. Methods. TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids. Results. Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R− subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA. Conclusions. De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients

Published
2019

9. High expression of adrenal P450 aromatase (CYP19A1) in association with ARMC5-primary bilateral macronodular adrenocortical hyperplasia

Author

Annabel Berthon, Andrea Gutierrez Maria, Fabio R. Faucz, Fady Hannah-Shmouni, and Constantine A. Stratakis

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Somatic cell, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Cushingoid, Biochemistry, Germline, Article, 03 medical and health sciences, Cushing syndrome, 0302 clinical medicine, Endocrinology, Aromatase, Internal medicine, Adrenal Glands, medicine, Humans, Point Mutation, Receptor, Molecular Biology, Cushing Syndrome, Armadillo Domain Proteins, biology, business.industry, Adrenal cortex, Tumor Suppressor Proteins, Cell Biology, Middle Aged, medicine.disease, Up-Regulation, 030104 developmental biology, medicine.anatomical_structure, Gynecomastia, 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine, business
Abstract

Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing syndrome (CS), which has been associated with ectopic G-protein coupled receptors (GPCRs) in the adrenal cortex. We recently studied a 51-year-old male with PBMAH who presented with severe CS and hyperestronemia, manifesting clinically with a cushingoid appearance, gynecomastia, telangiectasias and other signs of high estrogens. Hyperestronemia was further confirmed with aberrant responses to exogenous hCG. Analysis of adrenal tissues following bilateral adrenalectomy showed high expression of P450 aromatase (CYP19A1). The subject carried a germline non-sense pathogenic variant in ARMC5 (p.R173*), with two independent somatic pathogenic variants identified in the right (p.S571*) and left (p.Q235*) adrenal tissues, respectively. The expression of ARMC5 was drastically decreased in the hyperplastic regions when compared to either the adjacent non-hyperplastic regions and samples from PBMAH without pathogenic variants in ARMC5. We found expression of CYP19A1 in other cases of PBMAH, although there were no differences in aromatase expression between ARMC5- mutant and ARMC5-non-mutant cases. We conclude that in select cases, PBMAH can be associated with aromatase expression resulting in elevated estrogens, irrespective of sex. Additionally, CYP19A1 expression may not depend on the ARMC5 variant status.

Published
2019

10. OR02-6 Mass Spectrometry-Based Steroid Profiling Inprimary Bilateral Macronodular Adrenocortical Hyperplasia

Author

Mirko Peitzsch, Fady Hannah-Shmouni, Fideline Bonnet-Serrano, Jimmy Masjkur, Andrew P. Demidowich, Martin Reincke, Graeme Eisenhofer, Andrea Gutierrez Maria, Constantine A. Stratakis, Fabio R. Faucz, Jérôme Bertherat, Anna Vaczlavik, Annabel Berthon, and Juan Medina Briceno

Subjects
Updates in Adrenal Steroidogenesis, Therapeutics, and Cancer, business.industry, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, medicine, Cancer research, Adrenal, Mass spectrometry, business, Adrenocortical hyperplasia, Steroid
Abstract

Background: Biochemical characterization of primary bilateral macronodular adrenocortical hyperplasia (PBMAH) by distinct plasma steroid profiles and its putative correlation to disease has not been previously studied. Methods: LC-MS/MS-based steroid profiling of 16 plasma steroids was applied to 36 subjects (22 females, 14 males) with PBMAH, 19 subjects (16 females, 3 males) with other forms of adrenal CS (ACS), and an age and sex-matched control group. Germline ARMC5 sequencing was performed in all PBMAH cases. Results: The steroids showing the most dramatic differences between subject groups included 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, 18-hydroxycortisol, progesterone and DHEA/DHEA-S. Steroids that showed isolated differences included cortisol and 18-oxocortisol with higher (P

Published
2019

11. Trabecular bone score as skeletal fragility predictor in patients with acromegaly

Author

Carranza Federico Hawkins, Librizzi Maria Soledad, Iglesias Sonsoles Guadalix, Diaz-Guerra Guillermo Martinez, Mendez Violeta Gonzalez, Gutierrez Maria Calatayud, and Martin Laura Perez-Olivares

Subjects
medicine.medical_specialty, Trabecular bone score, Fragility, business.industry, Acromegaly, Urology, medicine, In patient, medicine.disease, business
Published
2018

12. Host kinin B1 receptor plays a protective role against melanoma progression

Author

Clara Nahmias, João Bosco Pesquero, Claudio M. Costa-Neto, Rosana I. Reis, Patricia Dillenburg-Pilla, Andrea Gutierrez Maria, Cristiane Tefé-Silva, Elaine M. Floriano, Simone G. Ramos, Department of Biochemistry and Immunology, University of São Paulo (USP), Department of Biophysics, Universidade Federal de Sao Paulo, Institut Cochin (IC UM3 (UMR 8104 / U1016)), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Lung Neoplasms, Skin Neoplasms, Mitotic index, Kallikrein-Kinin System, [SDV]Life Sciences [q-bio], Melanoma, Experimental, [SDV.CAN]Life Sciences [q-bio]/Cancer, Receptor, Bradykinin B1, Article, Metastasis, Mice, 03 medical and health sciences, 0302 clinical medicine, Mitotic Index, medicine, Animals, Receptor, Protein kinase B, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Multidisciplinary, business.industry, Melanoma, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Kinin, medicine.disease, Interleukin-10, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, 030104 developmental biology, 030220 oncology & carcinogenesis, Knockout mouse, Immunology, Disease Progression, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, business, Proto-Oncogene Proteins c-akt, CD8, Signal Transduction, PROGNÓSTICO
Abstract

Sao Paulo State Research Foundation (FAPESP) FAPESP Melanoma is a very aggressive tumor that arises from melanocytes. Late stage and widely spread diseases do not respond to standard therapeutic approaches. The kallikrein-kinin system (KKS) participates in biological processes such as vasodilatation, pain and inflammatory response. However, the role of KKS in tumor formation and progression is not completely understood. The role of the host kinin B1 receptor in melanoma development was evaluated using a syngeneic melanoma model. Primary tumors and metastasis were respectively induced by injecting B16F10 melanoma cells, which are derived from C57BL/6 mice, subcutaneously or in the tail vein in wild type C57BL/6 and B1 receptor knockout mice (B1(-/-)). Tumors developed in B1(-/-) mice presented unfavorable prognostic factors such as increased incidence of ulceration, higher levels of IL-10, higher activation of proliferative pathways such as ERK1/2 and Akt, and increased mitotic index. Furthermore, in the metastasis model, B1(-/-) mice developed larger metastatic colonies in the lung and lower CD8(+) immune effector cells when compared with WT animals. Altogether, our results provide evidences that B1(-/-) animals developed primary tumors with multiple features associated with poor prognosis and unfavorable metastatic onset, indicating that the B1 receptor may contribute to improve the host response against melanoma progression. Univ Sao Paulo, Dep Biochem & Immunol, BR-14049900 Ribeirao Preto, Brazil Univ Sao Paulo, Ribeirao Preto Med Sch, BR-14049900 Ribeirao Preto, Brazil Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol, BR-14049900 Ribeirao Preto, Brazil Univ Fed Sao Paulo, Dept Biophys, BR-04039032 Sao Paulo, Brazil Inst Gustave Roussy, INSERM, U981, F-94800 Villejuif, France Univ Fed Sao Paulo, Dept Biophys, BR-04039032 Sao Paulo, Brazil FAPESP: 2010/13346-4 FAPESP: 2012/20148-0 FAPESP: 2011/02144-4 Web of Science

Published
2016

13. Effect of iron supplementation on the erosive potential of carbonated or decarbonated beverage

Author

Melissa Thiemi Kato, Luís Guilherme Matiazi Vaz, Marília Afonso Rabelo Buzalaf, Andrea Gutierrez Maria, Sílvia Helena de Carvalho Sales-Peres, and Flávia de Moraes Italiani

Subjects
Tooth erosion, Chromatography, Materials science, Enamel paint, business.industry, Iron, Dental enamel, Dentistry, Demineralization, Phosphate, lcsh:RK1-715, chemistry.chemical_compound, chemistry, lcsh:Dentistry, visual_art, visual_art.visual_art_medium, Iron supplementation, Original Article, Bovine enamel, business, General Dentistry
Abstract

This study evaluated, in vitro, the effect of iron (previously exposed with enamel powder or added directly to the beverage) on the erosive potential of carbonated or decarbonated beverage. Four sets of experiments were done. For groups E1 and E3, a solution containing 30 mmol/L FeSO4 was added to bovine enamel powder (particles between 75-106 mm) before exposure to the carbonated or decarbonated beverage (Sprite Zero(R)), respectively. For groups E2 and E4, 15 mmol/L FeSO4 was added directly to the carbonated or decarbonated beverage, respectively. Control groups were included for comparison. In controls C1 and C3, the experiments E1 and E3 were repeated, but the iron solution was replaced by deionized water. For controls C2 and C4, the carbonated and decarbonated beverage, respectively, was used, without addition of iron. After addition of the beverage to the powdered enamel (40 mg enamel powder/400 mL of final volume), the sample was vortexed for 30 s and immediately centrifuged for 30 s (11,000 rpm). The supernatant was removed after 1 min 40 s. This procedure was repeated in quintuplicate and the phosphate released was analyzed spectrophotometrically. The results were analyzed by Student's t-test (p0.05). E2 presented the best results with a significant inhibition (around 36%) of phosphate released. For E3 and E4 a non-significant inhibition (around 4 and 12%, respectively), was observed. For E1 an increase in phosphate loss was detected. Thus, the protective effect of iron seems to be better when this ion is directly added to the carbonated beverage.

Published
2007

14. Fluoridation of the public water supply and prevalence of dental fluorosis in a peripheral district of the municipality of Bauru, SP

Author

Kelly Polido Kaneshiro Olympio, Carolina Simonetti Lodi, Irene Ramires, Andrea Gutierrez Maria, Vanessa Eid da Silva Cardoso, Marília Afonso Rabelo Buzalaf, Juliano Pelim Pessan, Universidade de São Paulo (USP), and Universidade Estadual Paulista (Unesp)

Subjects
Physics, Epidemiology, business.industry, Dentistry, medicine.disease, Fluorosis, Fluoridation, Sanitary surveillance, medicine, Original Article, Fluoride, business, General Dentistry, Humanities, Dental fluorosis
Abstract

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:21:55Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:45:41Z : No. of bitstreams: 1 2-s2.0-33745643579.pdf: 45033 bytes, checksum: 7dee5a7e4a45a999306123c600bc084c (MD5) Made available in DSpace on 2014-05-27T11:21:55Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-07-06 Objectives: The objectives of this study were to assess the fluoride concentration in the public water supply and the prevalence of dental fluorosis in schoolchildren between 7 and 15 years old, living in a peripheral district of the municipality of Bauru. Material and Methods: For this, fifty two water samples were collected on three different days of one week. These samples were analyzed for fluoride by means of the ion-sensitive electrode method (Orion 9609) coupled to a potentiometer (Procyon, model 720). In this method, 1.0 mL of TISAB II (Orion) was added to 1.0 mL of the sample. For the epidemiological survey of fluorosis, 52 schoolchildren of both genders, aged between 7 and 15 were assessed, with prior authorization from their caretakers. Only one person examined the children, after supervised toothbrushing and drying with cotton wool rolls. The TF index was used. Results: The fluoride concentrations in the water samples ranged from 0.62 to 1.20 mg/L, with a mean of 0.9 mg/L. The prevalence of dental fluorosis was 33%, with severity ranging from TF1 to TF4 (Kappa of 0.73 and concordance of 83.33%). Conclusions: The results from the analysis of water samples indicated a fluoride concentration greater than recommended for Bauru. The fluorosis levels found were higher than expected for a peripheral district, in which water is one of the few sources of fluoride. Bauru Dental School University of São Paulo Public Health School University of São Paulo Faculty of Sciences São Paulo State University Araçatuba Dental School São Paulo State University Institute of Chemistry University of São Paulo Universidade de São Paulo Faculdade de Odontologia de Bauru Área de Bioquímica, A. Dr. O. Pinheiro Brisolla, 9-75, Cep.: 17. 012-901 Bauru SP Faculty of Sciences São Paulo State University Araçatuba Dental School São Paulo State University

Published
2006

15. Kinetics of fluoride removal from plasma and bone of rats after chronic intake of fluoride

Author

Mileni da Silva Fernandes, E. E. Caroselli, Andrea Gutierrez Maria, Marília Afonso Rabelo Buzalaf, and Aline de Lima Leite

Subjects
musculoskeletal diseases, Chronic exposure, medicine.medical_specialty, Time Factors, Kinetics, Dentistry, Bone and Bones, chemistry.chemical_compound, Fluorides, Internal medicine, Blood plasma, medicine, Animals, Femur surface, Femur, Water fluoride, Tissue Distribution, Rats, Wistar, Minerals, Dose-Response Relationship, Drug, business.industry, Chemistry, musculoskeletal system, Cariostatic Agents, Rats, Endocrinology, Female, business, Fluoride, Bone surface
Abstract

This study evaluated the kinetics of fluoride in plasma, femur surface and the whole femur of rats, after chronic exposure to different water fluoride levels was interrupted. Four groups of Wistar rats received drinking water containing 0, 5, 15 or 50 microg F/ml for 60 days (n = 50/group). The animals were euthanized immediately after exposure to fluoride or after 7, 30, 90 or 180 days (n = 10/subgroup). Plasma and femurs were collected. Fluoride on the femur surface, whole femur and plasma was analyzed with an electrode. Data were analyzed using ANOVA and Tukey's test (p< 0.05). The increase in plasma fluoride levels was significant only for the 50 microg F/ml group at 0 and 7 days. Regarding bone surface and whole bone, for most groups, significant increases in fluoride concentrations were observed with the increase in water fluoride concentrations at each time of euthanasia. For fluoride doses up to 15 microg F/ml, femur surface fluoride levels were reestablished 180 days after the exposure was discontinued, which was not valid for whole femur or for higher fluoride doses. We found a different kinetics of fluoride in plasma, femur surface and the whole femur of rats after chronic exposure to fluoride is interrupted.

Published
2008

16. Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label

Author

Diaz-Lagares, Candido, Perez-Alvarez, Roberto, Garcia-Hernandez, Francisco J., Ayala-Gutierrez, Maria M., Luis Callejas, Jose, Martinez-Berriotxoa, Agustin, Rascon, Javier, Caminal-Montero, Luis, Selva-O'Callaghan, Albert, Oristrell, Joaquim, Hidalgo, Carmen, Gomez-de-la-Torre, Ricardo, Saez, Luis, Canora-Lebrato, Jesus, Camps, Maria-Teresa, Ortego-Centeno, Norberto, Castillo-Palma, Maria-Jesus, Ramos-Casals, Manuel, and BIOGEAS Study Grp

Subjects
Male, modelos de riesgos proporcionales, humanos, enfermedades autoinmunes, adolescente, Kaplan-Meier Estimate, vasculitis, Etanercept, rituximab, Infection rate, systemic lupus erythematosus, Risk Factors, adalimumab, Immunology and Allergy, Sjogren syndrome, Young adult, mediana edad, Aged, 80 and over, anciano, Middle Aged, adulto, adulto joven, Female, productos biológicos, Rituximab, prescripción en indicaciones no aprobadas, Infection, Vasculitis, Research Article, medicine.drug, Adult, estimación de Kaplan-Meier, medicine.medical_specialty, Adolescent, Immunology, macromolecular substances, Infections, Autoimmune Diseases, Young Adult, Rheumatology, Internal medicine, Adalimumab, medicine, Humans, factores de riesgo, Aged, Proportional Hazards Models, Biological Products, business.industry, Off-Label Use, infección, medicine.disease, Sjögren syndrome, Infliximab, Observational study, infliximab, business, etanercept
Abstract

Introduction: The purpose of this observational study was to analyze the rates, characteristics and associated risk factors of severe infections in patients with systemic autoimmune diseases (SAD) who were treated off-label with biological agents in daily practice. Methods: The BIOGEAS registry is an ongoing Spanish prospective cohort study investigating the long-term safety and efficacy of the off-label use of biological agents in adult patients with severe, refractory SAD. Severe infections were defined according to previous studies as those that required intravenous treatment or that led to hospitalization or death. Patients contributed person-years of follow-up for the period in which they were treated with biological agents. Results: A total of 344 patients with SAD treated with biological agents off-label were included in the Registry until July 2010. The first biological therapies included rituximab in 264 (77%) patients, infliximab in 37 (11%), etanercept in 21 (6%), adalimumab in 19 (5%), and 'other' agents in 3 (1%). Forty-five severe infections occurred in 37 patients after a mean follow-up of 26.76 months. These infections resulted in four deaths. The crude rate of severe infections was 90.9 events/1000 person-years (112.5 for rituximab, 76.9 for infliximab, 66.9 for adalimumab and 30.5 for etanercept respectively). In patients treated with more than two courses of rituximab, the crude rate of severe infection was 226.4 events/1000 person-years. A pathogen was identified in 24 (53%) severe infections. The most common sites of severe infection were the lower respiratory tract (39%), bacteremia/sepsis (20%) and the urinary tract (16%). There were no significant differences relating to gender, SAD, agent, other previous therapies, number of previous immunosuppressive agents received or other therapies administered concomitantly. Cox regression analysis showed that age (P = 0.015) was independently associated with an increased risk of severe infection. Survival curves showed a lower survival rate in patients with severe infections (log-rank and Breslow tests < 0.001). Conclusions: The rates of severe infections in SAD patients with severe, refractory disease treated depended on the biological agent used, with the highest rates being observed for rituximab and the lowest for etanercept. The rate of infection was especially high in patients receiving three or more courses of rituximab. In patients with severe infections, survival was significantly reduced. Older age was the only significant predictive factor of severe infection., The BIOGEAS Study group has received educational grants from Roche and Abbott supporting the design and maintenance of the webpage [35]. All authors have declared no conflicts of interest. None has received grants from these laboratories or conducted clinical trials with rituximab or etanercept as principal investigators or received honoraria as an Advisory Board member for Roche and Abbott. The financial support of Roche and Abbott is exclusively limited to maintaining the BIOGEAS webpage.

Published
2011

17. Nilotinib first-line therapy in patients with Philadelphia chromosome-negative/BCR-ABL-positive chronic myeloid leukemia in chronic phase:ENEST1st sub-analysis

Author

Maria Liz Paciello Coronel, Beatrice Vincenzi, Ljubomir Petrov, Fausto Castagnetti, Delphine Rea, Andrzej Hellmann, Francis J. Giles, Andreas Hochhaus, Valentin Garcia-Gutierrez, Maria Asuncion Echeveste Gutierrez, Franҫois-Xavier Mahon, Luca Dezzani, Philipp le Coutre, Gianantonio Rosti, Norbert Gattermann, Nicholas C.P. Cross, Jeroen Janssen, CCA - Cancer Treatment and quality of life, Hematology, Hochhaus, Andrea, Mahon, Franois-Xavier, le Coutre, Philipp, Petrov, Ljubomir, Janssen, Jeroen J. W. M., Cross, Nicholas C. P., Rea, Delphine, Castagnetti, Fausto, Hellmann, Andrzej, Rosti, Gianantonio, Gattermann, Norbert, Coronel, Maria Liz Paciello, Gutierrez, Maria Asuncion Echeveste, Garcia-Gutierrez, Valentin, Vincenzi, Beatrice, Dezzani, Luca, and Giles, Francis J.

Subjects
Male, 0301 basic medicine, Cancer Research, Myeloid, Original Article – Clinical Oncology, Fusion Proteins, bcr-abl, Gastroenterology, Antineoplastic Agent, 0302 clinical medicine, hemic and lymphatic diseases, Philadelphia Chromosome, Hematology, Chronic myeloid leukemia, Myeloid leukemia, General Medicine, Middle Aged, Leukemia, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Female, Human, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Anemia, Philadelphia Chromosome Negative, Protein Kinase Inhibitor, Antineoplastic Agents, Real-Time Polymerase Chain Reaction, Philadelphia chromosome, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Philadelphia chromosome negative/BCR-ABL positive, Protein Kinase Inhibitors, Aged, ENEST1st, business.industry, Nilotinib, medicine.disease, Pyrimidines, 030104 developmental biology, Pyrimidine, business, Multiplex Polymerase Chain Reaction
Abstract

PURPOSE: The ENEST1st sub-analysis presents data based on Philadelphia chromosome (Ph) status, i.e., Ph+ and Ph-/BCR-ABL1 + chronic myeloid leukemia.METHODS: Patients received nilotinib 300 mg twice daily, up to 24 months.RESULTS: At screening, 983 patients were identified as Ph+ and 30 patients as Ph-/BCR-ABL + based on cytogenetic and RT-PCR assessment; 76 patients had unknown karyotype (excluded from this sub-analysis). In the Ph-/BCR-ABL1 + subgroup, no additional chromosomal aberrations were reported. In the Ph+ subgroup, 952 patients had safety and molecular assessments. In the Ph-/BCR-ABL1 + subgroup, 30 patients had safety assessments and 28 were followed up for molecular assessments. At 18 months, the molecular response (MR) 4 rate [MR4; BCR-ABL1 ≤0.01% on International Scale (IS)] was similar in the Ph-/BCR-ABL1+ (39.3%) and Ph+ subgroups (38.1%). By 24 months, the cumulative rates of major molecular response (BCR-ABL1IS≤0.1%;), MR4, and MR4.5(BCR-ABL1IS≤0.0032%) were 85.7, 60.7, and 50.0%, respectively, in the Ph-/BCR-ABL1 + subgroup, and 80.3, 54.7, and 38.3%, respectively, in the Ph+ subgroup. In both Ph-/BCR-ABL1 + and Ph+ subgroups, rash (20 and 22%), pruritus (16.7 and 16.7%), nasopharyngitis (13.3 and 10.4%), fatigue (10 and 14.2%), headache (10 and 15.8%), and nausea (6.7 vs 11.4%) were frequent non-hematologic adverse events, whereas hypophosphatemia (23.3 and 6.8%), anemia (10 and 6.5%), and thrombocytopenia (3.3 and 10.2%) were the common hematologic/biochemical laboratory events.CONCLUSION: Based on similar molecular response and safety results in both subgroups, we conclude that Ph-/BCR-ABL1 + patients benefit from nilotinib in the same way as Ph+ patients.

Published
2017

18. Executive summary of the SEPAR recommendations for the diagnosis and treatment of non-small cell lung cancer

Author

Eva de Higes Martinez, Ignacio Muguruza Trueba, Carlos A. Rombolá, Jorge Freixinet Gilart, Raúl Embún Flor, Juan José Rivas de Andrés, Pablo Gámez García, Pablo León Atance, Iñigo San Miguel Arregui, Fátima Hermoso Alarza, Andrea Mariscal de Alba, Gonzalo Varela Simó, Felipe Villar Álvarez, Laura Mezquita Pérez, Primitivo Martínez Vallina, Esther Barreiro, Segismundo Solano Reina, Carmen Vallejo, M. Henar Borrego Pintado, Maria Eugenia Olmedo Garcia, José Ignacio de Granda Orive, Régulo José Ávila Martínez, Pilar López, Carlos Disdier Vicente, Carlos A. Jiménez Ruiz, María Dolores García Jiménez, Pedro Rodríguez Suárez, David Aguiar Bujanda, José Miguel Izquierdo Elena, Laureano Molins López-Rodó, Patricia Menal Muñoz, Paz Vaquero Lozano, José Belda Sanchis, Luis Seijo Maceiras, Iker López Sanz, Íñigo Royo Crespo, Ángel Salvatierra Velázquez, Samuel Hernandez Sarmiento, Nuria María Novoa Valentín, Vicente Diaz-Hellín Gude, Antonio Francisco Honguero Martínez, María de Valle Somiedo Gutiérrez, Javier Flandes Aldeyturriaga, Javier J. Zulueta, Julio Sánchez de Cos Escuín, Joan Carles Trujillo Reyes, Ana Isabel Triviño Ramírez, [Villar Alvarez, Felipe] UAM, CIBERES, IIS Fdn Jimenez Diaz, Serv Neumol, Madrid, Spain, [Muguruza Trueba, Ignacio] Hosp Idcsalud, Dept Cirugia Torac, Madrid, Spain, [Belda Sanchis, Jose] Hosp Univ Mutua Terrassa, Serv Cirugia Torac, Barcelona, Spain, [Trujillo Reyes, Joan Caries] Hosp Univ Mutua Terrassa, Serv Cirugia Torac, Barcelona, Spain, [Molins Lopez-Rodo, Laureano] Hosp Clin Barcelona, Inst Clin Respiratori, Serv Cirugia Torac, Barcelona, Spain, [Rodriguez Suarez, Pedro Miguel] Hosp Univ Gran Canaria Dr Negrin, Serv Cirugia Torac, Las Palmas Gran Canaria, Las Palmas, Spain, [Freixinet Gilarte, Jorge L.] Hosp Univ Gran Canaria Dr Negrin, Serv Cirugia Torac, Las Palmas Gran Canaria, Las Palmas, Spain, [de Cos Escuin, Julio Sanchez] Hosp San Pedro Alcantara, Sec Neumol, Caceres, Spain, [Barreiro, Esther] Univ Pompeu Fabra, Hosp del Mar, Inst Salud Carlos III,Grp Invest Desgaste Muscula, Ctr Invest Red Enfermedades Resp CIBERES,Inst Inv, PRBB, Barcelona, Spain, [Borrego Pintado, M. Henar] Hosp Clin Univ, Serv Anat Patol, Valladolid, Spain, [Disdier Vicente, Carlos] Hosp Clin Univ, Serv Neumol, Valladolid, Spain, [Flandes Aldeyturriaga, Javier] UAM, ISS Fdn Jimenez Diaz, CIBERES, Serv Neumol,Unidad Broncoscopias & Neumol Interve, Madrid, Spain, [Somiedo Gutierrez, Maria de Valle] UAM, ISS Fdn Jimenez Diaz, CIBERES, Serv Neumol,Unidad Broncoscopias & Neumol Interve, Madrid, Spain, [Gamez Garcia, Pablo] Hosp Univ 12 Octubre, Serv Cirugia Torac, Madrid, Spain, [Avila Martinez, Regulo J.] Hosp Univ 12 Octubre, Serv Cirugia Torac, Madrid, Spain, [Diaz-Hellin Gude, Vicente] Hosp Univ 12 Octubre, Serv Cirugia Torac, Madrid, Spain, [Hermoso Alarza, Fatima] Hosp Univ 12 Octubre, Serv Cirugia Torac, Madrid, Spain, [Mariscal de Alba, Andrea] Hosp Univ 12 Octubre, Serv Cirugia Torac, Madrid, Spain, [Garrido Lopez, Pilar] Hosp Univ Ramon Y Cajal, Serv Oncol Med, Madrid, Spain, [Perez, Laura Mezquita] Hosp Univ Ramon Y Cajal, Serv Oncol Med, Madrid, Spain, [Garcia, Maria Eugenia Olmedo] Hosp Univ Ramon Y Cajal, Serv Oncol Med, Madrid, Spain, [Leon Atance, Pablo] Complejo Hosp Univ Albacete, Serv Cirugia Torac, Albacete, Spain, [Garcia Jimenez, Maria Dolores] Complejo Hosp Univ Albacete, Serv Cirugia Torac, Albacete, Spain, [Honguero Martinez, Antonio Francisco] Complejo Hosp Univ Albacete, Serv Cirugia Torac, Albacete, Spain, [Rombolda, Carlos A.] Complejo Hosp Univ Albacete, Serv Cirugia Torac, Albacete, Spain, [Trivino Ramirez, Ana Isabel] Complejo Hosp Univ Albacete, Serv Cirugia Torac, Albacete, Spain, [Izquierdo Elena, Jose Miguel] Hosp Univ Donostia, Serv Cirugia Torac, Donostia San Sebastian, Gipuzkoa, Spain, [Lopez Sanz, Iker] Hosp Univ Donostia, Serv Cirugia Torac, Donostia San Sebastian, Gipuzkoa, Spain, [Novoa Valentin, Nuria M.] Complejo Asistencial Univ Salamanca, Serv Cirugia Torac, Salamanca, Spain, [Varela Simo, Gonzalo] Complejo Asistencial Univ Salamanca, Serv Cirugia Torac, Salamanca, Spain, [Rivas de Andres, Juan Jose] Hosp Clin Univ Lozano Blesa & IIS Aragon, Hosp Univ Miguel Servet, Zaragoza, Spain, [Royo Crespo, Iriigo] Hosp Clin Univ Lozano Blesa & IIS Aragon, Hosp Univ Miguel Servet, Zaragoza, Spain, [Embun Flor, Raul] Hosp Clin Univ Lozano Blesa & IIS Aragon, Hosp Univ Miguel Servet, Zaragoza, Spain, [Martinez Vallina, Primitivo] Hosp Clin Univ Lozano Blesa & IIS Aragon, Hosp Univ Miguel Servet, Zaragoza, Spain, [Salvatierra Velazquez, Angel] Hosp Univ Reina Sofia, Unidad Cirugia Torac & Trasplante Pulmonar, Cordoba, Spain, [Seijo Maceiras, Luis M.] IIS Fdn Jimenez Diaz CIBERES, Serv Neumol, Madrid, Spain, [Solano Reina, Segismundo] HGU Gregorio Maranon, Serv Neumol, Unidad Tabaquismo, Madrid, Spain, [Vaquero Lozano, Paz] HGU Gregorio Maranon, Serv Neumol, Unidad Tabaquismo, Madrid, Spain, [Aguiar Bujanda, David] Hosp Univ Gran Canaria Dr Negrin, Serv Oncol Med, Las Palmas Gran Canaria, Las Palmas, Spain, [Hernandez Sarmiento, Samuel] Hosp Univ Gran Canaria Dr Negrin, Serv Oncol Med, Las Palmas Gran Canaria, Las Palmas, Spain, [de Granda Orive, Jose Ignacio] Hosp 12 Octubre, Serv Neumol, Madrid, Spain, [de Higes Martinez, Eva] Fdn Hosp Alcorcon, Serv Neumol, Madrid, Spain, [Jimenez Ruiz, Carlos A.] Comunidad Autonoma Madrid, Unidad Especializada Tabaquismo, Madrid, Spain, [Menal Munoz, Patricia] Hosp Clin Univ Lozano Blesa, Serv Radiol, Zaragoza, Spain, [Miguel Arregui, Iffigo San] Hosp Univ Gran Canaria Dr Negrin, Serv Oncol Radioterap, Las Palmas Gran Canaria, Las Palmas, Spain, [Vallejo, Carmen] Hosp Univ Ramon Y Cajal, Serv Oncol Radioterap, Madrid, Spain, and [Zulueta, Javier J.] Univ Navarra Clin, Serv Neumol, Pamplona, Spain

Subjects
Lung Neoplasms, Transbronchial needle aspiration, medicine.medical_treatment, Disease, Recommendations, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Positron Emission Tomography Computed Tomography, Diagnosis, Pulmonary Medicine, Medicine, Respiratory function, Stage (cooking), Pneumonectomy, Early Detection of Cancer, Societies, Medical, Palliative Care, Clinical-practice guidelines, Staging project, General Medicine, Chemoradiotherapy, Esmo consensus conference, Pulmonology, Cardiothoracic surgery, Tnm classification, 030220 oncology & carcinogenesis, Radiology, Lung cancer, International-association, medicine.medical_specialty, Ed american-college, Diagnostic Techniques, Respiratory System, Forthcoming 7th edition, 03 medical and health sciences, Internal medicine, Thoracic Oncology, Bronchoscopy, Biomarkers, Tumor, Humans, Intensive care medicine, Neoplasm Staging, Salvage Therapy, Low-dose ct, business.industry, Induction chemoradiation, medicine.disease, Treatment, Radiation therapy, 030228 respiratory system, Spain, Smoking Cessation, business, Tomography, X-Ray Computed
Abstract

The Thoracic Surgery and Thoracic Oncology groups of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) have backed the publication of a handbook on recommendations for the diagnosis and treatment of non-small cell lung cancer. Due to the high incidence and mortality of this disease, the best scientific evidence must be constantly updated and made available for consultation by healthcare professionals.To draw up these recommendations, we called on a wide-ranging group of experts from the different specialties, who have prepared a comprehensive review, divided into 4 main sections. The first addresses disease prevention and screening, including risk factors, the role of smoking cessation, and screening programs for early diagnosis. The second section analyzes clinical presentation, imaging studies, and surgical risk, including cardiological risk and the evaluation of respiratory function. The third section addresses cytohistological confirmation and staging studies, and scrutinizes the TNM and histological classifications, non-invasive and minimally invasive sampling methods, and surgical techniques for diagnosis and staging. The fourth and final section looks at different therapeutic aspects, such as the role of surgery, chemotherapy, radiation therapy, a multidisciplinary approach according to disease stage, and other specifically targeted treatments, concluding with recommendations on the follow-up of lung cancer patients and surgical and endoscopic palliative interventions in advanced stages. (C) 2016 SEPAR. Published by Elsevier Espana, S.L.U. All rights reserved.

Published
2015

19. Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

Author

Alm E., Broberg E.K., Connor T., Hodcroft E.B., Komissarov A.B., Maurer-Stroh S., Melidou A., Neher R.A., O'Toole A., Pereyaslov D., Beerenwinkel N., Posada-Cespedes S., Jablonski K.P., Ferreira P.F., Topolsky I., Avsic-Zupanc T., Korva M., Poljak M., Zakotnik S., Zorec T.M., Bragstad K., Hungnes O., Stene-Johansen K., Reusken C., Meijer A., Vennema H., Ruiz-Roldan L., Bracho M.A., Garcia-Gonzalez N., Chiner-Oms A., Cancino-Munoz I., Comas I., Goig G.A., Torres-Puente M., Lopez M.G., Martinez-Priego L., D'Auria G., Ruiz-Hueso P., Ferrus-Abad L., de Marco G., Galan-Vendrell I., Carbo-Ramirez S., Ruiz-Rodriguez P., Coscolla M., Polackova K., Kramna L., Cinek O., Richter J., Krashias G., Tryfonos C., Bashiardes S., Koptides D., Christodoulou C., Bartolini B., Gruber C.E., Di Caro A., Castilletti C., Stefani F., Rimoldi S.G., Romeri F., Salerno F., Polesello S., Nagy A., Jirincova H., Vecerova J., Novakova L., Cordey S., Murtskhvaladze M., Kotaria N., Schar T., Beisel C., Vugrek O., Rokic F., Trgovec-Greif L., Jurak I., Rukavina T., Sucic N., Schonning K., Karst S.M., Kirkegaard R.H., Michaelsen T.Y., Sorensen E.A., Knutson S., Brandt J., Le-Quy V., Sorensen T., Petersen C., Pedersen M.S., Larsen S.L., Skov M.N., Rasmussen M., Fonager J., Fomsgaard A., Maksyutov R.A., Gavrilova E.V., Pyankov O.V., Bodnev S.A., Tregubchak T.V., Shvalov A.N., Antonets D.V., Resende P.C., Goya S., Perrin A., Lee R.T., Yadahalli S., Han A.X., Russell C.A., Schmutz S., Zaheri M., Kufner V., Huber M., Trkola A., Antwerpen M., Walter M.C., van der Werf S., Gambaro F., Behillil S., Enouf V., Donati F., Ustinova M., Rovite V., Klovins J., Savicka O., Wienecke-Baldacchino A.K., Ragimbeau C., Fournier G., Mossong J., Aberle S.W., Haukland M., Enkirch T., Advani A., Karlberg M.L., Lindsjo O.K., Broddesson S., Slavikova M., Lickova M., Klempa B., Staronova E., Ticha E., Szemes T., Rusnakova D., Stadler T., Quer J., Anton A., Andres C., Pinana M., Garcia-Cehic D., Pumarola T., Izopet J., Gioula G., Exindari M., Papa A., Chatzidimitriou D., Metallidis S., Pappa S., Macek M., Geryk J., Broz P., Briksi A., Hubacek P., Drevinek P., Zajac M., Kvapil P., Holub M., Kvapilova K., Novotny A., Kasny M., Klempt P., Vapalahti O., Smura T., Sironen T., Selhorst P., Anthony C., Arien K., Simon-Loriere E., Rabalski L., Bienkowska-Szewczyk K., Borges V., Isidro J., Gomes J.P., Guiomar R., Pechirra P., Costa I., Duarte S., Vieira L., Pyrc K., Zuckerman N.S., Turdikulova S., Abdullaev A., Dalimova D., Abdurakhimov A., Tagliabracci A., Alessandrini F., Melchionda F., Onofri V., Turchi C., Bagnarelli P., Menzo S., Caucci S., Di Sante L., Popa A., Genger J.-W., Agerer B., Lercher A., Endler L., Smyth M., Penz T., Schuster M., Senekowitsch M., Laine J., Bock C., Bergthaler A., Shevtsov A., Kalendar R., Ramanculov Y., Graf A., Muenchhoff M., Keppler O.T., Krebs S., Blum H., Marcello A., Licastro D., D'Agaro P., Laubscher F., Vidanovic D., Tesovic B., Volkening J., Clementi N., Mancini N., Rupnik M., Mahnic A., Walker A., Houwaart T., Wienemann T., Vasconcelos M.K., Strelow D., Jensen B.-E.O., Senff T., Hulse L., Adams O., Andree M., Hauka S., Feldt T., Keitel V., Kindgen-Milles D., Timm J., Pfeffer K., Dilthey A.T., Moore C., Ozdarendeli A., Pavel S.T.I., Yetiskin H., Aydin G., Holyavkin C., Uygut M.A., Cevik C., Shchetinin A., Gushchin V., Dinler-Doganay G., Doganay L., Kizilboga-Akgun T., Karacan I., Pancer K., Maes P., Marti-Carreras J., Wawina-Bokalanga T., Vanmechelen B., Thurmer A., Wedde M., Durrwald R., von Kleist M., Drechsel O., Wolff T., Fuchs S., Kmiecinski R., Michel J., Nitsche A., Casas I., Caballero M.I., Zaballos A., Jimenez P., Jimenez M., Fernandez S.M., Fernandez S.V., de la Plaza I.C., Fadeev A., Ivanova A., Sergeeva M., Stefanelli P., Estee Torok M., Hall G., da Silva Filipe A., Turtle L., Afifi S., McCluggage K., Beer R., Ledesma J., Maksimovic J., Spellman K., Hamilton W.L., Marchbank A., Southgate J.A., Underwood A., Taylor B., Yeats C., Abudahab K., Gemmell M.R., Eccles R., Lucaci A., Nelson C.A., Rainbow L., Whitehead M., Gregory R., Haldenby S., Paterson S., Hughes M.A., Curran M.D., Baker D., Tucker R., Green L.R., Feltwell T., Halstead F.D., Wyles M., Jahun A.S., Ahmad S.S.Y., Georgana I., Goodfellow I., Yakovleva A., Meredith L.W., Gavriil A., Awan A.R., Fisher C., Edgeworth J., Lynch J., Moore N., Williams R., Kidd S.P., Cortes N., Brunker K., McCrone J.T., Quick J., Duckworth N., Walsh S., Sloan T., Ludden C., George R.P., Eltringham G., Brown J.R., Aranday-Cortes E., Shepherd J.G., Hughes J., Li K.K., Williams T.C., Johnson N., Jesudason N., Mair D., Thomson E., Shah R., Parr Y.A., Carmichael S., Robertson D.L., Nomikou K., Broos A., Niebel M., Smollett K., Tong L., Miah S., Wittner A., Phillips N., Payne B., Dewar R., Holmes A., Bolt F., Price J.R., Mookerjee S., Sethi D.K., Potter W., Stanley R., Prakash R., Dervisevic S., Graham J.C., Nelson A., Smith D., Young G.R., Yew W.C., Todd J.A., Trebes A., Andersson M., Bull M., Watkins J., Birchley A., Gatica-Wilcox B., Gilbert L., Kumziene-Summerhayes S., Rey S., Chauhan A., Butcher E., Bicknell K., Elliott S., Glaysher S., Lackenby A., Bibby D., Platt S., Mohamed H., Machin N.W., Mbisa J.L., Evans J., Perry M., Pacchiarini N., Corden S., Adams A.G., Gaskin A., Coombs J., Graham L.J., Cottrell S., Morgan M., Gifford L., Kolyva A., Rudder S.J., Trotter A.J., Mather A.E., Aydin A., Page A.J., Kay G.L., de Oliveira Martins L., Yasir M., Alikhan N.-F., Thomson N.M., Gilroy R., Kingsley R.A., O'Grady J., Gutierrez A.V., Diaz M., Viet T.L., Tedim A.P., Adriaenssens E.M., Patrick Mcclure C., Sang F., Clark G., Howson-Wells H.C., Debebe J., Ball J., Chappell J., Khakh M., Carlile M., Loose M., Lister M.M., Holmes N., Tsoleridis T., Fleming V.M., Wright V., Smith W., Gallagher M.D., Parker M., Partridge D.G., Evans C., Baker P., Essex S., Liggett S., Keeley A.J., Bashton M., Rooke S., Dervisavic S., Meader E.J., Lopez C.E.B., Angyal A., Kristiansen M., Tutill H.J., Findlay J., Mestek-Boukhibar L., Forrest L., Dyal P., Williams R.J., Panchbhaya Y., Williams C.A., Roy S., Pandey S., Stockton J., Loman N.J., Poplawski R., Nicholls S., Rowe W.P.M., Khokhar F., Pinckert M.L., Hosmillo M., Chaudhry Y., Caller L.G., Davidson R.K., Griffith L., Rambaut A., Jackson B., Colquhoun R., Hill V., Nichols J., Asamaphan P., Darby A., Jackson K.A., Iturriza-Gomara M., Vamos E.E., Green A., Aanensen D., Bonsall D., Buck D., Macintyre-Cockett G., de Cesare M., Pybus O., Golubchik T., Scarlett G., Loveson K.F., Robson S.C., Beckett A., Lindsey B., Groves D.C., Parsons P.J., McHugh M.P., Barnes J.D., Manso C.F., Grammatopoulos D., Menger K.E., Harrison E., Gunson R., Peacock S.J., Gonzalez G., Carr M., Mihaela L., Popovici O., Brytting M., Bresner C., Fuller W., Workman T., Mentis A.F., Kossyvakis A., Karamitros T., Pogka V., Kalliaropoulos A., Horefti E., Kontou A., Martinez-Gonzalez B., Labropoulou V., Voulgari-Kokota A., Evangelidou M., Bizta P., Belimezi M., Lambrechts L., Doymaz M.Z., Yazici M.K., Cetin N.S., Karaaslan E., Kallio-Kokko H., Virtanen J., Suvanto M., Nguyen P.T., Ellonen P., Hannula S., Kangas H., Sreenu V.B., Burian K., Terhes G., Gombos K., Gyenesei A., Urban P., Herczeg R., Jakab F., Kemenesi G., Toth G.E., Somogyi B., Zana B., Zeghbib S., Kuczmog A., Foldes F., Lanszki Z., Madai M., Papp H., Pereszlenyi C.I., Babinszky G.C., Dudas G., Csoma E., Abou Tayoun A.N., Alsheikh-Ali A.A., Loney T., Nowotny N., Abdul-Wahab O., Gonzalez-Candelas F., Andersen M.H., Taylor S., MARTI CARRERAS, Joan, Vanmechelen, Bert, Wawina, Tony, Medical Microbiology and Infection Prevention, AII - Infectious diseases, WHO European Region Sequencing Lab, GISAID EpiCoV Grp, Erik, Alm, Eeva K, Broberg, Thomas, Connor, Emma B, Hodcroft, Andrey B, Komissarov, Sebastian, Maurer-Stroh, Angeliki, Melidou, Richard A, Neher, Áine, O’Toole, Dmitriy, Pereyaslov, WHO European Region sequencing laboratories and GISAID EpiCoV group (Niko Beerenwinkel, The, Posada-Céspedes, Susana, Philipp, Kim, Jablonski, Falé Ferreira, Pedro, Topolsky, Ivan, Avšičžupanc, Tatjana, Korva, Miša, Poljak, Mario, Zakotnik, Samo, Tomaž, Zorec, Mark, Bragstad, Karoline, Hungnes, Olav, Stene-Johansen, Kathrine, Reusken, Chantal, Meijer, Adam, Vennema, Harry, Ruiz-Roldán, Lidia, Alma Bracho, María, García-González, Neri, Chiner-Oms, Álvaro, Cancino-Muñoz, Irving, Comas, Iñaki, A Goig, Galo, Torres-Puente, Manuela, G López, Mariana, Martínez-Priego, Llúcia, D’Auria, Giuseppe, LoretoFerrús-Abad, de Marco, Griselda, Galan-Vendrell, Inmaculada, Carbó-Ramirez, Sandra, Ruíz-Hueso, Paula, Coscollá, Mireia, Polackova, Katerina, Kramna, Lenka, Cinek, Ondrej, Richter, Jan, Krashias, George, Tryfonos, Christina, Bashiardes, Stavro, Koptides, Dana, Christodoulou, Christina, Bartolini, Barbara, Em Gruber, Cesare, Di Caro, Antonino, Castilletti, Concetta, Stefani, Fabrizio, Giordana Rimoldi, Sara, Romeri, Francesca, Salerno, Franco, Polesello, Stefano, Nagy, Alexander, Jirincova, Helena, Vecerova, Jaromira, Novakova, Ludmila, Cordey, Samuel, Murtskhvaladze, Marine, Kotaria, Nato, Schär, Tobia, Beisel, Christian, Vugrek, Oliver, Rokić, Filip, Trgovecgreif, Lovro, Jurak, Igor, Rukavina, Tomislav, Sučić, Neven, Schønning, Kristian, M Karst, Søren, H Kirkegaard, Rasmu, Y Michaelsen, Thoma, Aa Sørensen, Emil, Knutson, Simon, Brandt, Jakob, Le-Quy, Vang, Sørensen, Trine, Petersen, Celine, Schou Pedersen, Martin, Løkkegaard Larsen, Sanne, Nielsine Skov, Marianne, Rasmussen, Morten, Fonager, Jannik, Fomsgaard, Ander, Amirovich Maksyutov, Rinat, Vasil’Evna Gavrilova, Elena, Victorovich Pyankov, Oleg, Alexandrovich Bodnev, Sergey, Vladimirovna Tregubchak, Tatyana, Nikolayevich Shvalov, Alexander, Victorovich Antonets, Deni, Cristina Resende, Paola, Goya, Stephanie, Perrin, Amandine, Tc Lee, Raphael, Yadahalli, Shilpa, X Han, Alvin, A Russell, Colin, Schmutz, Stefan, Zaheri, Maryam, Kufner, Verena, Huber, Michael, Trkola, Alexandra, Antwerpen, Marku, C Walter, Mathia, van der Werf, Sylvie, Gambaro, Fabiana, Behillil, Sylvie, Enouf, Vincent, Donati, Flora, Ustinova, Monta, Rovite, Vita, Klovins, Jani, Savicka, Oksana, K Wienecke-Baldacchino, Anke, Ragimbeau, Catherine, Fournier, Guillaume, Mossong, Joël, W Aberle, Stephan, Haukland, Mattia, Enkirch, Theresa, Advani, Abdolreza, Lind Karlberg, Maria, Karlsson Lindsjö, Oskar, Broddesson, Sandra, Sláviková, Monika, Ličková, Martina, Klempa, Bori, Staroňová, Edita, Tichá, Elena, Szemes, Tomáš, Rusňáková, Diana, Stadler, Tanja, Quer, Josep, Anton, Andre, Andres, Cristina, Piñana, Maria, Garcia-Cehic, Damir, Pumarola, Toma, Izopet, Jacque, Gioula, Georgia, Exindari, Maria, Papa, Anna, Chatzidimitriou, Dimitrio, Metallidis, Symeon, Pappa, Stella, Macek Jr, Milan, Geryk, Jan, Brož, Petr, Briksí, Aleš, Hubáček, Petr, Dřevínek, Pavel, Zajac, Miroslav, Kvapil, Petr, Holub, Michal, Kvapilová, Kateřina, Novotný, Adam, Kašný, Martin, Klempt, Petr, Vapalahti, Olli, Smura, Teemu, Sironen, Tarja, Selhorst, Philippe, Anthony, Colin, Ariën, Kevin, Simon-Loriere, Etienne, Rabalski, Lukasz, Bienkowska-Szewczyk, Krystyna, Borges, Vítor, Isidro, Joana, Paulo Gomes, João, Guiomar, Raquel, Pechirra, Pedro, Costa, Inê, Duarte, Sílvia, Vieira, Luí, Pyrc, Krzysztof, S Zuckerman, Neta, Turdikulova, Shahlo, Abdullaev, Alisher, Dalimova, Dilbar, Abdurakhimov, Abror, Tagliabracci, Adriano, Alessandrini, Federica, Melchionda, Filomena, Onofri, Valerio, Turchi, Chiara, Bagnarelli, Patrizia, Menzo, Stefano, Caucci, Sara, Di Sante, Laura, Popa, Alexandra, Genger, Jakob-Wendelin, Agerer, Benedikt, Lercher, Alexander, Endler, Luka, Smyth, Mark, Penz, Thoma, Schuster, Michael, Senekowitsch, Martin, Laine, Jan, Bock, Christoph, Bergthaler, Andrea, Shevtsov, Alexandr, Kalendar, Ruslan, Ramanculov, Yerlan, Graf, Alexander, Muenchhoff, Maximilian, T Keppler, Oliver, Krebs, Stefan, Blum, Helmut, Marcello, Alessandro, Licastro, Danilo, D’Agaro, Pierlanfranco, Laubscher, Florian, Vidanovic, Dejan, Tesovic, Bojana, Volkening, Jeremy, Clementi, Nicola, Mancini, Nicasio, Rupnik, Maja, Mahnic, Aleksander, Walker, Andrea, Houwaart, Torsten, Wienemann, Tobia, Kohns Vasconcelos, Malte, Strelow, Daniel, Ole Jensen, Björn-Erik, Senff, Tina, Hülse, Lisanna, Adams, Ortwin, Andree, Marcel, Hauka, Sandra, Feldt, Torsten, Keitel, Verena, Kindgen-Milles, Detlef, Timm, Jörg, Pfeffer, Klau, T Dilthey, Alexander, Moore, Catherine, Ozdarendeli, Aykut, Terkis Islam Pavel, Shaikh, Yetiskin, Hazel, Aydin, Gunsu, Holyavkin, Can, Ali Uygut, Muhammet, Cevik, Ceren, Shchetinin, Alexey, Gushchin, Vladimir, Dinler-Doganay, Gizem, Doganay, Levent, Kizilboga-Akgun, Tugba, Karacan, Ilker, Pancer, Katarzyna, Maes, Piet, Martí-Carreras, Joan, Wawina-Bokalanga, Tony, Thürmer, Andrea, Wedde, Marianne, Dürrwald, Ralf, Von Kleist, Max, Drechsel, Oliver, Wolff, Thorsten, Fuchs, Stephan, Kmiecinski, Rene, Michel, Janine, Nitsche, Andrea, Casas, Inmaculada, Iglesias Caballero, María, Zaballos, Ángel, Jiménez, Pilar, Jiménez, Mercede, Monzón Fernández, Sara, Varona Fernández, Sarai, Cuesta De La Plaza, Isabel, Fadeev, Artem, Ivanova, Anna, Sergeeva, Mariia, Stefanelli, Paola, Estee Torok, M, Hall, Grant, da Silva Filipe, Ana, Turtle, Lance, Afifi, Safiah, Mccluggage, Kathryn, Beer, Robert, Ledesma, Juan, Maksimovic, Joshua, Spellman, Karla, L Hamilton, William, Marchbank, Angela, Alexander Southgate, Joel, Underwood, Anthony, Taylor, Ben, Yeats, Corin, Abudahab, Khalil, R Gemmell, Matthew, Eccles, Richard, Lucaci, Anita, Abigail Nelson, Charlotte, Rainbow, Lucille, Whitehead, Mark, Gregory, Richard, Haldenby, Sam, Paterson, Steve, A Hughes, Margaret, D Curran, Martin, Baker, David, Tucker, Rachel, R Green, Luke, Feltwell, Theresa, D Halstead, Fenella, Wyles, Matthew, S Jahun, Aminu, Y Ahmad, Shazaad S, Georgana, Iliana, Goodfellow, Ian, Yakovleva, Anna, W Meredith, Luke, Gavriil, Artemi, Raza Awan, Ali, Fisher, Chloe, Jonathan, European Centre for Disease Prevention and Control [Stockholm, Sweden] (ECDC), Cardiff University, Public Health Wales [Cardiff, Royaume uni], University of Basel (Unibas), Research Institute of Influenza, St. Petersburg, Russia, Agency for science, technology and research [Singapore] (A*STAR), National University of Singapore (NUS), University of Edinburgh, WHO Regional Office for Europe [Copenhagen], We gratefully acknowledge the authors, originating and submitting laboratories of the sequences from GISAID’s EpiCoV Database used in the phylogenetic analysis. We gratefully acknowledge all the staff working with sample collection, sample preparation, sequencing, data analysis and data sharing in all laboratories in the WHO European Region for making this work possible, The WHO European Region sequencing laboratories and GISAID EpiCoV group*: Niko Beerenwinkel, Susana Posada-Céspedes, Kim Philipp Jablonski, Pedro Falé Ferreira, Ivan Topolsky, Tatjana Avšič-Županc, Miša Korva, Mario Poljak, Samo Zakotnik, Tomaž Mark Zorec, Karoline Bragstad, Olav Hungnes, Kathrine Stene-Johansen, Chantal Reusken, Adam Meijer, Harry Vennema, Lidia Ruiz-Roldán, María Alma Bracho, Neris García-González, Álvaro Chiner-Oms, Irving Cancino-Muñoz, Iñaki Comas, Galo A Goig, Manuela Torres-Puente, Mariana G López, Llúcia Martínez-Priego, Giuseppe D'Auria, Paula Ruíz-Hueso, Loreto Ferrús-Abad, Griselda de Marco, Inmaculada Galan-Vendrell, Sandra Carbó-Ramirez, Paula Ruiz-Rodriguez, Mireia Coscollá, Katerina Polackova, Lenka Kramna, Ondrej Cinek, Jan Richter, George Krashias, Christina Tryfonos, Stavros Bashiardes, Dana Koptides, Christina Christodoulou, Barbara Bartolini, Cesare Em Gruber, Antonino Di Caro, Concetta Castilletti, Fabrizio Stefani, Sara Giordana Rimoldi, Francesca Romeri, Franco Salerno, Stefano Polesello, Alexander Nagy, Helena Jirincova, Jaromira Vecerova, Ludmila Novakova, Samuel Cordey, Marine Murtskhvaladze, Nato Kotaria, Tobias Schär, Christian Beisel, Oliver Vugrek, Filip Rokić, Lovro Trgovec-Greif, Igor Jurak, Tomislav Rukavina, Neven Sučić, Kristian Schønning, Søren M Karst, Rasmus H Kirkegaard, Thomas Y Michaelsen, Emil Aa Sørensen, Simon Knutson, Jakob Brandt, Vang Le-Quy, Trine Sørensen, Celine Petersen, Martin Schou Pedersen, Sanne Løkkegaard Larsen, Marianne Nielsine Skov, Morten Rasmussen, Jannik Fonager, Anders Fomsgaard, Rinat Amirovich Maksyutov, Elena Vasil'Evna Gavrilova, Oleg Victorovich Pyankov, Sergey Alexandrovich Bodnev, Tatyana Vladimirovna Tregubchak, Alexander Nikolayevich Shvalov, Denis Victorovich Antonets, Paola Cristina Resende, Stephanie Goya, Amandine Perrin, Raphael Tc Lee, Shilpa Yadahalli, Alvin X Han, Colin A Russell, Stefan Schmutz, Maryam Zaheri, Verena Kufner, Michael Huber, Alexandra Trkola, Markus Antwerpen, Mathias C Walter, Sylvie van der Werf, Fabiana Gambaro, Sylvie Behillil, Vincent Enouf, Flora Donati, Monta Ustinova, Vita Rovite, Janis Klovins, Oksana Savicka, Anke K Wienecke-Baldacchino, Catherine Ragimbeau, Guillaume Fournier, Joël Mossong, Stephan W Aberle, Mattias Haukland, Theresa Enkirch, Abdolreza Advani, Maria Lind Karlberg, Oskar Karlsson Lindsjö, Sandra Broddesson, Monika Sláviková, Martina Ličková, Boris Klempa, Edita Staroňová, Elena Tichá, Tomáš Szemes, Diana Rusňáková, Tanja Stadler, Josep Quer, Andres Anton, Cristina Andres, Maria Piñana, Damir Garcia-Cehic, Tomas Pumarola, Jacques Izopet, Georgia Gioula, Maria Exindari, Anna Papa, Dimitrios Chatzidimitriou, Symeon Metallidis, Stella Pappa, Milan Macek Jr, Jan Geryk, Petr Brož, Aleš Briksí, Petr Hubáček, Pavel Dřevínek, Miroslav Zajac, Petr Kvapil, Michal Holub, Kateřina Kvapilová, Adam Novotný, Martin Kašný, Petr Klempt, Olli Vapalahti, Teemu Smura, Tarja Sironen, Philippe Selhorst, Colin Anthony, Kevin Ariën, Etienne Simon-Loriere, Lukasz Rabalski, Krystyna Bienkowska-Szewczyk, Vítor Borges, Joana Isidro, João Paulo Gomes, Raquel Guiomar, Pedro Pechirra, Inês Costa, Sílvia Duarte, Luís Vieira, Krzysztof Pyrc, Neta S Zuckerman, Shahlo Turdikulova, Alisher Abdullaev, Dilbar Dalimova, Abror Abdurakhimov, Adriano Tagliabracci, Federica Alessandrini, Filomena Melchionda, Valerio Onofri, Chiara Turchi, Patrizia Bagnarelli, Stefano Menzo, Sara Caucci, Laura Di Sante, Alexandra Popa, Jakob-Wendelin Genger, Benedikt Agerer, Alexander Lercher, Lukas Endler, Mark Smyth, Thomas Penz, Michael Schuster, Martin Senekowitsch, Jan Laine, Christoph Bock, Andreas Bergthaler, Alexandr Shevtsov, Ruslan Kalendar, Yerlan Ramanculov, Alexander Graf, Maximilian Muenchhoff, Oliver T Keppler, Stefan Krebs, Helmut Blum, Alessandro Marcello, Danilo Licastro, Pierlanfranco D'Agaro, Florian Laubscher, Dejan Vidanovic, Bojana Tesovic, Jeremy Volkening, Nicola Clementi, Nicasio Mancini, Maja Rupnik, Aleksander Mahnic, Andreas Walker, Torsten Houwaart, Tobias Wienemann, Malte Kohns Vasconcelos, Daniel Strelow, Björn-Erik Ole Jensen, Tina Senff, Lisanna Hülse, Ortwin Adams, Marcel Andree, Sandra Hauka, Torsten Feldt, Verena Keitel, Detlef Kindgen-Milles, Jörg Timm, Klaus Pfeffer, Alexander T Dilthey, Catherine Moore, Aykut Ozdarendeli, Shaikh Terkis Islam Pavel, Hazel Yetiskin, Gunsu Aydin, Can Holyavkin, Muhammet Ali Uygut, Ceren Cevik, Alexey Shchetinin, Vladimir Gushchin, Gizem Dinler-Doganay, Levent Doganay, Tugba Kizilboga-Akgun, Ilker Karacan, Katarzyna Pancer, Piet Maes, Joan Martí-Carreras, Tony Wawina-Bokalanga, Bert Vanmechelen, Andrea Thürmer, Marianne Wedde, Ralf Dürrwald, Max Von Kleist, Oliver Drechsel, Thorsten Wolff, Stephan Fuchs, Rene Kmiecinski, Janine Michel, Andreas Nitsche, Inmaculada Casas, María Iglesias Caballero, Ángel Zaballos, Pilar Jiménez, Mercedes Jiménez, Sara Monzón Fernández, Sarai Varona Fernández, Isabel Cuesta De La Plaza, Artem Fadeev, Anna Ivanova, Mariia Sergeeva, Paola Stefanelli, M Estee Torok, Grant Hall, Ana da Silva Filipe, Lance Turtle, Safiah Afifi, Kathryn Mccluggage, Robert Beer, Juan Ledesma, Joshua Maksimovic, Karla Spellman, William L Hamilton, Angela Marchbank, Joel Alexander Southgate, Anthony Underwood, Ben Taylor, Corin Yeats, Khalil Abudahab, Matthew R Gemmell, Richard Eccles, Anita Lucaci, Charlotte Abigail Nelson, Lucille Rainbow, Mark Whitehead, Richard Gregory, Sam Haldenby, Steve Paterson, Margaret A Hughes, Martin D Curran, David Baker, Rachel Tucker, Luke R Green, Theresa Feltwell, Fenella D Halstead, Matthew Wyles, Aminu S Jahun, Shazaad S Y Ahmad, Iliana Georgana, Ian Goodfellow, Anna Yakovleva, Luke W Meredith, Artemis Gavriil, Ali Raza Awan, Chloe Fisher, Jonathan Edgeworth, Jessica Lynch, 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Ethan Butcher, Kelly Bicknell, Scott Elliott, Sharon Glaysher, Angie Lackenby, David Bibby, Steven Platt, Hodan Mohamed, Nicholas William Machin, Jean Lutamyo Mbisa, Jonathan Evans, Malorie Perry, Nicole Pacchiarini, Sally Corden, Alexander Geraint Adams, Amy Gaskin, Jason Coombs, Lee John Graham, Simon Cottrell, Mari Morgan, Laura Gifford, Anastasia Kolyva, Steven John Rudder, Alexander J Trotter, Alison E Mather, Alp Aydin, Andrew J Page, Gemma L Kay, Leonardo de Oliveira Martins, Muhammad Yasir, Nabil-Fareed Alikhan, Nicholas M Thomson, Rachel Gilroy, Robert A Kingsley, Justin O'Grady, Ana Victoria Gutierrez, Maria Diaz, Thanh Le Viet, Ana P Tedim, Evelien M Adriaenssens, C Patrick Mcclure, Christopher Moore, Fei Sang, Gemma Clark, Hannah C Howson-Wells, Johnny Debebe, Jonathan Ball, Joseph Chappell, Manjinder Khakh, Matthew Carlile, Matthew Loose, Michelle M Lister, Nadine Holmes, Theocharis Tsoleridis, Vicki M Fleming, Victoria Wright, Wendy Smith, Michael D Gallagher, Matthew 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H., Taylor, S., European Centre for Disease Prevention and Control (ECDC), Public Health Wales Microbiology Cardiff, Faculty of Agriculture and Forestry, Department of Agricultural Sciences, and Institute of Biotechnology

Subjects
Infecções Respiratórias, 0301 basic medicine, MESH: Coronavirus Infections, Epidemiology, [SDV]Life Sciences [q-bio], Distribution (economics), Wastewater, MESH: Base Sequence, Severe Acute Respiratory Syndrome, MESH: World Health Organization, Pandemic, MESH: Coronavirus, MESH: COVID-19, Sequencing, Viral, Clade, Nomenclature, Genome, biology, COVID-19, Europe, NGS, SARS-CoV-2, WGS, nomenclature, sequencing, Base Sequence, Betacoronavirus, Coronavirus, Coronavirus Infections, Genome, Viral, Humans, Phylogeography, Pneumonia, Viral, RNA, Viral, RNA-Dependent RNA Polymerase, Spatio-Temporal Analysis, World Health Organization, Pandemics, C500, European region, 3. Good health, Geography, MESH: Phylogeography, MESH: RNA-Dependent RNA Polymerase, MESH: RNA, Viral, MESH: Betacoronavirus, Spatio-Temporal Analysi, MESH: Genome, Viral, Cartography, Human, Bioquímica, MESH: Pandemics, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Coronaviru, 030106 microbiology, 03 medical and health sciences, MESH: Spatio-Temporal Analysis, MESH: Severe Acute Respiratory Syndrome, Virology, MESH: SARS-CoV-2, Whole genome sequencing, MESH: Humans, Whole Genome Sequencing, Betacoronaviru, Coronavirus Infection, business.industry, Public Health, Environmental and Occupational Health, Pneumonia, biology.organism_classification, B900, 030104 developmental biology, MESH: Pneumonia, Viral, RNA, SARS_CoV-2, 3111 Biomedicine, MESH: Europe, Human medicine, business
Abstract

8 páginas, 3 figuras, We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2., We gratefully acknowledge the authors, originating and submitting laboratories of the sequences from GISAID’s EpiCoV Database used in the phylogenetic analysis. We gratefully acknowledge all the staff working with sample collection, sample preparation, sequencing, data analysis and data sharing in all laboratories in the WHO European Region for making this work possible.

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