Regional Selection Acting on the OFD1 Gene Family

The OFD1 (oral-facial-digital, type 1) gene is implicated in several developmental disorders in humans. The X-linked OFD1 (OFD1X) is conserved in Eutheria. Knowledge about the Y-linked paralog (OFD1Y) is limited. In this study, we identified an OFD1Y on the bovine Y chromosome, which is expressed differentially from the bovine OFD1X. Phylogenetic analysis indicated that: a) the eutherian OFD1X and OFD1Y were derived from the pair of ancestral autosomes during sex chromosome evolution; b) the autosomal OFD1 pseudogenes, present in Catarrhini and Murinae, were derived from retropositions of OFD1X after the divergence of primates and rodents; and c) the presence of OFD1Y in the ampliconic region of the primate Y chromosome is an indication that the expansion of the ampliconic region may initiate from the X-degenerated sequence. In addition, we found that different regions of OFD1/OFD1X/OFD1Y are under differential selection pressures. The C-terminal half of OFD1 is under relaxed selection with an elevated Ka/Ks ratio and clustered positively selected sites, whereas the N-terminal half is under stronger constraints. This study provides some insights into why the OFD1X gene causes OFD1 (male-lethal X-linked dominant) and SGBS2 & JSRDs (X-linked recessive) syndromes in humans, and reveals the origin and evolution of the OFD1 family, which will facilitate further clinical investigation of the OFD1-related syndromes

Association between loop diuretic dose changes and outcomes in chronic heart failure: observations from the ESC-EORP Heart Failure Long-Term Registry

[Abstract] Aims. Guidelines recommend down-titration of loop diuretics (LD) once euvolaemia is achieved. In outpatients with heart failure (HF), we investigated LD dose changes in daily cardiology practice, agreement with guideline recommendations, predictors of successful LD down-titration and association between dose changes and outcomes. Methods and results. We included 8130 HF patients from the ESC-EORP Heart Failure Long-Term Registry. Among patients who had dose decreased, successful decrease was defined as the decrease not followed by death, HF hospitalization, New York Heart Association class deterioration, or subsequent increase in LD dose. Mean age was 66±13 years, 71% men, 62% HF with reduced ejection fraction, 19% HF with mid-range ejection fraction, 19% HF with preserved ejection fraction. Median [interquartile range (IQR)] LD dose was 40 (25–80) mg. LD dose was increased in 16%, decreased in 8.3% and unchanged in 76%. Median (IQR) follow-up was 372 (363–419) days. Diuretic dose increase (vs. no change) was associated with HF death [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.12–2.08; P = 0.008] and nominally with cardiovascular death (HR 1.25, 95% CI 0.96–1.63; P = 0.103). Decrease of diuretic dose (vs. no change) was associated with nominally lower HF (HR 0.59, 95% CI 0.33–1.07; P = 0.083) and cardiovascular mortality (HR 0.62 95% CI 0.38–1.00; P = 0.052). Among patients who had LD dose decreased, systolic blood pressure [odds ratio (OR) 1.11 per 10 mmHg increase, 95% CI 1.01–1.22; P = 0.032], and absence of (i) sleep apnoea (OR 0.24, 95% CI 0.09–0.69; P = 0.008), (ii) peripheral congestion (OR 0.48, 95% CI 0.29–0.80; P = 0.005), and (iii) moderate/severe mitral regurgitation (OR 0.57, 95% CI 0.37–0.87; P = 0.008) were independently associated with successful decrease. Conclusion. Diuretic dose was unchanged in 76% and decreased in 8.3% of outpatients with chronic HF. LD dose increase was associated with worse outcomes, while the LD dose decrease group showed a trend for better outcomes compared with the no-change group. Higher systolic blood pressure, and absence of (i) sleep apnoea, (ii) peripheral congestion, and (iii) moderate/severe mitral regurgitation were independently associated with successful dose decrease

Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P\ua0 64 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P\ua0=\ua00.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P\ua075 years. Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF 6445%

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Acute heart failure congestion and perfusion status – impact of the clinical classification on in-hospital and long-term outcomes; insights from the ESC-EORP-HFA Heart Failure Long-Term Registry

none614siAims: Classification of acute heart failure (AHF) patients into four clinical profiles defined by evidence of congestion and perfusion is advocated by the 2016 European Society of Cardiology (ESC)guidelines. Based on the ESC-EORP-HFA Heart Failure Long-Term Registry, we compared differences in baseline characteristics, in-hospital management and outcomes among congestion/perfusion profiles using this classification. Methods and results: We included 7865 AHF patients classified at admission as: ‘dry-warm’ (9.9%), ‘wet-warm’ (69.9%), ‘wet-cold’ (19.8%) and ‘dry-cold’ (0.4%). These groups differed significantly in terms of baseline characteristics, in-hospital management and outcomes. In-hospital mortality was 2.0% in ‘dry-warm’, 3.8% in ‘wet-warm’, 9.1% in ‘dry-cold’ and 12.1% in ‘wet-cold’ patients. Based on clinical classification at admission, the adjusted hazard ratios (95% confidence interval) for 1-year mortality were: ‘wet-warm’ vs. ‘dry-warm’ 1.78 (1.43–2.21) and ‘wet-cold’ vs. ‘wet-warm’ 1.33 (1.19–1.48). For profiles resulting from discharge classification, the adjusted hazard ratios (95% confidence interval) for 1-year mortality were: ‘wet-warm’ vs. ‘dry-warm’ 1.46 (1.31–1.63) and ‘wet-cold’ vs. ‘wet-warm’ 2.20 (1.89–2.56). Among patients discharged alive, 30.9% had residual congestion, and these patients had higher 1-year mortality compared to patients discharged without congestion (28.0 vs. 18.5%). Tricuspid regurgitation, diabetes, anaemia and high New York Heart Association class were independently associated with higher risk of congestion at discharge, while beta-blockers at admission, de novo heart failure, or any cardiovascular procedure during hospitalization were associated with lower risk of residual congestion. Conclusion: Classification based on congestion/perfusion status provides clinically relevant information at hospital admission and discharge. A better understanding of the clinical course of the two entities could play an important role towards the implementation of targeted strategies that may improve outcomes.noneChioncel O.; Mebazaa A.; Maggioni A.P.; Harjola V.-P.; Rosano G.; Laroche C.; Piepoli M.F.; Crespo-Leiro M.G.; Lainscak M.; Ponikowski P.; Filippatos G.; Ruschitzka F.; Seferovic P.; Coats A.J.S.; Lund L.H.; Auer J.; Ablasser K.; Fruhwald F.; Dolze T.; Brandner K.; Gstrein S.; Poelzl G.; Moertl D.; Reiter S.; Podczeck-Schweighofer A.; Muslibegovic A.; Vasilj M.; Fazlibegovic E.; Cesko M.; Zelenika D.; Palic B.; Pravdic D.; Cuk D.; Vitlianova K.; Katova T.; Velikov T.; Kurteva T.; Gatzov P.; Kamenova D.; Antova M.; Sirakova V.; Krejci J.; Mikolaskova M.; Spinar J.; Krupicka J.; Malek F.; Hegarova M.; Lazarova M.; Monhart Z.; Hassanein M.; Sobhy M.; El Messiry F.; El Shazly A.H.; Elrakshy Y.; Youssef A.; Moneim A.A.; Noamany M.; Reda A.; Dayem T.K.A.; Farag N.; Halawa S.I.; Hamid M.A.; Said K.; Saleh A.; Ebeid H.; Hanna R.; Aziz R.; Louis O.; Enen M.A.; Ibrahim B.S.; Nasr G.; Elbahry A.; Sobhy H.; Ashmawy M.; Gouda M.; Aboleineen W.; Bernard Y.; Luporsi P.; Meneveau N.; Pillot M.; Morel M.; Seronde M.-F.; Schiele F.; Briand F.; Delahaye F.; Damy T.; Eicher J.-C.; de Groote P.; Fertin M.; Lamblin N.; Isnard R.; Lefol C.; Thevenin S.; Hagege A.; Jondeau G.; Logeart D.; Le Marcis V.; Ly J.-F.; Coisne D.; Lequeux B.; Le Moal V.; Mascle S.; Lotton P.; Behar N.; Donal E.; Thebault C.; Ridard C.; Reynaud A.; Basquin A.; Bauer F.; Codjia R.; Galinier M.; Tourikis P.; Stavroula M.; Tousoulis D.; Stefanadis C.; Chrysohoou C.; Kotrogiannis I.; Matzaraki V.; Dimitroula T.; Karavidas A.; Tsitsinakis G.; Kapelios C.; Nanas J.; Kampouri H.; Nana E.; Kaldara E.; Eugenidou A.; Vardas P.; Saloustros I.; Patrianakos A.; Tsaknakis T.; Evangelou S.; Nikoloulis N.; Tziourganou H.; Tsaroucha A.; Papadopoulou A.; Douras A.; Polgar L.; Merkely B.; Kosztin A.; Nyolczas N.; Nagy A.C.; Halmosi R.; Elber J.; Alony I.; Shotan A.; Fuhrmann A.V.; Amir O.; Romano S.; Marcon S.; Penco M.; Di Mauro M.; Lemme E.; Carubelli V.; Rovetta R.; Metra M.; Bulgari M.; Quinzani F.; Lombardi C.; Bosi S.; Schiavina G.; Squeri A.; Barbieri A.; Di Tano G.; Pirelli S.; Ferrari R.; Fucili A.; Passero T.; Musio S.; Di Biase M.; Correale M.; Salvemini G.; Brognoli S.; Zanelli E.; Giordano A.; Agostoni P.; Italiano G.; Salvioni E.; Copelli S.; Modena M.G.; Reggianini L.; Valenti C.; Olaru A.; Bandino S.; Deidda M.; Mercuro G.; Dessalvi C.C.; Marino P.N.; Di Ruocco M.V.; Sartori C.; Piccinino C.; Parrinello G.; Licata G.; Torres D.; Giambanco S.; Busalacchi S.; Arrotti S.; Novo S.; Inciardi R.M.; Pieri P.; Chirco P.R.; Galifi M.A.; Teresi G.; Buccheri D.; Minacapelli A.; Veniani M.; Frisinghelli A.; Priori S.G.; Cattaneo S.; Opasich C.; Gualco A.; Pagliaro M.; Mancone M.; Fedele F.; Cinque A.; Vellini M.; Scarfo I.; Romeo F.; Ferraiuolo F.; Sergi D.; Anselmi M.; Melandri F.; Leci E.; Iori E.; Bovolo V.; Pidello S.; Frea S.; Bergerone S.; Botta M.; Canavosio F.G.; Gaita F.; Merlo M.; Cinquetti M.; Sinagra G.; Ramani F.; Fabris E.; Stolfo D.; Artico J.; Miani D.; Fresco C.; Daneluzzi C.; Proclemer A.; Cicoira M.; Zanolla L.; Marchese G.; Torelli F.; Vassanelli C.; Voronina N.; Erglis A.; Tamakauskas V.; Smalinskas V.; Karaliute R.; Petraskiene I.; Kazakauskaite E.; Rumbinaite E.; Kavoliuniene A.; Vysniauskas V.; Brazyte-Ramanauskiene R.; Petraskiene D.; Stankala S.; Switala P.; Juszczyk Z.; Sinkiewicz W.; Gilewski W.; Pietrzak J.; Orzel T.; Kasztelowicz P.; Kardaszewicz P.; Lazorko-Piega M.; Gabryel J.; Mosakowska K.; Bellwon J.; Rynkiewicz A.; Raczak G.; Lewicka E.; Dabrowska-Kugacka A.; Bartkowiak R.; Sosnowska-Pasiarska B.; Wozakowska-Kaplon B.; Krzeminski A.; Zabojszcz M.; Mirek-Bryniarska E.; Grzegorzko A.; Bury K.; Nessler J.; Zalewski J.; Furman A.; Broncel M.; Poliwczak A.; Bala A.; Zycinski P.; Rudzinska M.; Jankowski L.; Kasprzak J.D.; Michalak L.; Soska K.W.; Drozdz J.; Huziuk I.; Retwinski A.; Flis P.; Weglarz J.; Bodys A.; Grajek S.; Kaluzna-Oleksy M.; Straburzynska-Migaj E.; Dankowski R.; Szymanowska K.; Grabia J.; Szyszka A.; Nowicka A.; Samcik M.; Wolniewicz L.; Baczynska K.; Komorowska K.; Poprawa I.; Komorowska E.; Sajnaga D.; Zolbach A.; Dudzik-Plocica A.; Abdulkarim A.-F.; Lauko-Rachocka A.; Kaminski L.; Kostka A.; Cichy A.; Ruszkowski P.; Splawski M.; Fitas G.; Szymczyk A.; Serwicka A.; Fiega A.; Zysko D.; Krysiak W.; Szabowski S.; Skorek E.; Pruszczyk P.; Bienias P.; Ciurzynski M.; Welnicki M.; Mamcarz A.; Folga A.; Zielinski T.; Rywik T.; Leszek P.; Sobieszczanska-Malek M.; Piotrowska M.; Kozar-Kaminska K.; Komuda K.; Wisniewska J.; Tarnowska A.; Balsam P.; Marchel M.; Opolski G.; Kaplon-Cieslicka A.; Gil R.J.; Mozenska O.; Byczkowska K.; Gil K.; Pawlak A.; Michalek A.; Krzesinski P.; Piotrowicz K.; Uzieblo-Zyczkowska B.; Stanczyk A.; Skrobowski A.; Ponikowski P.; Jankowska E.; Rozentryt P.; Polonski L.; Gadula-Gacek E.; Nowalany-Kozielska E.; Kuczaj A.; Kalarus Z.; Szulik M.; Przybylska K.; Klys J.; Prokop-Lewicka G.; Kleinrok A.; Aguiar C.T.; Ventosa A.; Pereira S.; Faria R.; Chin J.; De Jesus I.; Santos R.; Silva P.; Moreno N.; Queiros C.; Lourenco C.; Pereira A.; Castro A.; Andrade A.; Guimaraes T.O.; Martins S.; Placido R.; Lima G.; Brito D.; Francisco A.R.; Cardiga R.; Proenca M.; Araujo I.; Marques F.; Fonseca C.; Moura B.; Leite S.; Campelo M.; Silva-Cardoso J.; Rodrigues J.; Rangel I.; Martins E.; Correia A.S.; Peres M.; Marta L.; da Silva G.F.; Severino D.; Durao D.; Leao S.; Magalhaes P.; Moreira I.; Cordeiro A.F.; Ferreira C.; Araujo C.; Ferreira A.; Baptista A.; Radoi M.; Bicescu G.; Vinereanu D.; Sinescu C.-J.; Macarie C.; Popescu R.; Daha I.; Dan G.-A.; Stanescu C.; Dan A.; Craiu E.; Nechita E.; Aursulesei V.; Christodorescu R.; Otasevic P.; Seferovic P.M.; Simeunovic D.; Ristic A.D.; Celic V.; Pavlovic-Kleut M.; Lazic J.S.; Stojcevski B.; Pencic B.; Stevanovic A.; Andric A.; Iric-Cupic V.; Jovic M.; Davidovic G.; Milanov S.; Mitic V.; Atanaskovic V.; Antic S.; Pavlovic M.; Stanojevic D.; Stoickov V.; Ilic S.; Ilic M.D.; Petrovic D.; Stojsic S.; Kecojevic S.; Dodic S.; Adic N.C.; Cankovic M.; Stojiljkovic J.; Mihajlovic B.; Radin A.; Radovanovic S.; Krotin M.; Klabnik A.; Goncalvesova E.; Pernicky M.; Murin J.; Kovar F.; Kmec J.; Semjanova H.; Strasek M.; Iskra M.S.; Ravnikar T.; Suligoj N.C.; Komel J.; Fras Z.; Jug B.; Glavic T.; Losic R.; Bombek M.; Krajnc I.; Krunic B.; Horvat S.; Kovac D.; Rajtman D.; Cencic V.; Letonja M.; Winkler R.; Valentincic M.; Melihen-Bartolic C.; Bartolic A.; Vrckovnik M.P.; Kladnik M.; Pusnik C.S.; Marolt A.; Klen J.; Drnovsek B.; Leskovar B.; Anguita M.J.F.; Page J.C.G.; Martinez F.M.S.; Andres J.; Bayes-Genis A.; Mirabet S.; Mendez A.; Garcia-Cosio L.; Roig E.; Leon V.; Gonzalez-Costello J.; Muntane G.; Garay A.; Alcade-Martinez V.; Fernandez S.L.; Rivera-Lopez R.; Puga-Martinez M.; Fernandez-Alvarez M.; Serrano-Martinez J.L.; Crespo-Leiro M.; Grille-Cancela Z.; Marzoa-Rivas R.; Blanco-Canosa P.; Paniagua-Martin M.J.; Barge-Caballero E.; Cerdena I.L.; Baldomero I.F.H.; Padron A.L.; Rosillo S.O.; Gonzalez-Gallarza R.D.; Montanes O.S.; Manjavacas A.M.I.; Conde A.C.; Araujo A.; Soria T.; Garcia-Pavia P.; Gomez-Bueno M.; Cobo-Marcos M.; Alonso-Pulpon L.; Cubero J.S.; Sayago I.; Gonzalez-Segovia A.; Briceno A.; Subias P.E.; Hernandez M.V.; Cano M.J.R.; Sanchez M.A.G.; Jimenez J.F.D.; Garrido-Lestache E.B.; Pinilla J.M.G.; de la Villa B.G.; Sahuquillo A.; Marques R.B.; Calvo F.T.; Perez-Martinez M.T.; Gracia-Rodenas M.R.; Garrido-Bravo I.P.; Pastor-Perez F.; Pascual-Figal D.A.; Molina B.D.; Orus J.; Gonzalo F.E.; Bertomeu V.; Valero R.; Martinez-Abellan R.; Quiles J.; Rodrigez-Ortega J.A.; Mateo I.; ElAmrani A.; Fernandez-Vivancos C.; Valero D.B.; Almenar-Bonet L.; Sanchez-Lazaro I.J.; Marques-Sule E.; Facila-Rubio L.; Perez-Silvestre J.; Garcia-Gonzalez P.; Ridocci-Soriano F.; Garcia-Escriva D.; Pellicer-Cabo A.; de la Fuente Galan L.; Diaz J.L.; Platero A.R.; Arias J.C.; Blasco-Peiro T.; Julve M.S.; Sanchez-Insa E.; Aured-Guallar C.; Portoles-Ocampo A.; Melin M.; Hagglund E.; Stenberg A.; Lindahl I.-M.; Asserlund B.; Olsson L.; Dahlstrom U.; Afzelius M.; Karlstrom P.; Tengvall L.; Wiklund P.-A.; Olsson B.; Kalayci S.; Temizhan A.; Cavusoglu Y.; Gencer E.; Yilmaz M.B.; Gunes H.Chioncel, O.; Mebazaa, A.; Maggioni, A. P.; Harjola, V. -P.; Rosano, G.; Laroche, C.; Piepoli, M. F.; Crespo-Leiro, M. G.; Lainscak, M.; Ponikowski, P.; Filippatos, G.; Ruschitzka, F.; Seferovic, P.; Coats, A. J. S.; Lund, L. H.; Auer, J.; Ablasser, K.; Fruhwald, F.; Dolze, T.; Brandner, K.; Gstrein, S.; Poelzl, G.; Moertl, D.; Reiter, S.; Podczeck-Schweighofer, A.; Muslibegovic, A.; Vasilj, M.; Fazlibegovic, E.; Cesko, M.; Zelenika, D.; Palic, B.; Pravdic, D.; Cuk, D.; Vitlianova, K.; Katova, T.; Velikov, T.; Kurteva, T.; Gatzov, P.; Kamenova, D.; Antova, M.; Sirakova, V.; Krejci, J.; Mikolaskova, M.; Spinar, J.; Krupicka, J.; Malek, F.; Hegarova, M.; Lazarova, M.; Monhart, Z.; Hassanein, M.; Sobhy, M.; El Messiry, F.; El Shazly, A. H.; Elrakshy, Y.; Youssef, A.; Moneim, A. A.; Noamany, M.; Reda, A.; Dayem, T. K. A.; Farag, N.; Halawa, S. I.; Hamid, M. A.; Said, K.; Saleh, A.; Ebeid, H.; Hanna, R.; Aziz, R.; Louis, O.; Enen, M. A.; Ibrahim, B. S.; Nasr, G.; Elbahry, A.; Sobhy, H.; Ashmawy, M.; Gouda, M.; Aboleineen, W.; Bernard, Y.; Luporsi, P.; Meneveau, N.; Pillot, M.; Morel, M.; Seronde, M. -F.; Schiele, F.; Briand, F.; Delahaye, F.; Damy, T.; Eicher, J. -C.; de Groote, P.; Fertin, M.; Lamblin, N.; Isnard, R.; Lefol, C.; Thevenin, S.; Hagege, A.; Jondeau, G.; Logeart, D.; Le Marcis, V.; Ly, J. -F.; Coisne, D.; Lequeux, B.; Le Moal, V.; Mascle, S.; Lotton, P.; Behar, N.; Donal, E.; Thebault, C.; Ridard, C.; Reynaud, A.; Basquin, A.; Bauer, F.; Codjia, R.; Galinier, M.; Tourikis, P.; Stavroula, M.; Tousoulis, D.; Stefanadis, C.; Chrysohoou, C.; Kotrogiannis, I.; Matzaraki, V.; Dimitroula, T.; Karavidas, A.; Tsitsinakis, G.; Kapelios, C.; Nanas, J.; Kampouri, H.; Nana, E.; Kaldara, E.; Eugenidou, A.; Vardas, P.; Saloustros, I.; Patrianakos, A.; Tsaknakis, T.; Evangelou, S.; Nikoloulis, N.; Tziourganou, H.; Tsaroucha, A.; Papadopoulou, A.; Douras, A.; Polgar, L.; Merkely, B.; Kosztin, A.; Nyolczas, N.; Nagy, A. C.; Halmosi, R.; Elber, J.; Alony, I.; Shotan, A.; Fuhrmann, A. V.; Amir, O.; Romano, S.; Marcon, S.; Penco, M.; Di Mauro, M.; Lemme, E.; Carubelli, V.; Rovetta, R.; Metra, M.; Bulgari, M.; Quinzani, F.; Lombardi, C.; Bosi, S.; Schiavina, G.; Squeri, A.; Barbieri, A.; Di Tano, G.; Pirelli, S.; Ferrari, R.; Fucili, A.; Passero, T.; Musio, S.; Di Biase, M.; Correale, M.; Salvemini, G.; Brognoli, S.; Zanelli, E.; Giordano, A.; Agostoni, P.; Italiano, G.; Salvioni, E.; Copelli, S.; Modena, M. G.; Reggianini, L.; Valenti, C.; Olaru, A.; Bandino, S.; Deidda, M.; Mercuro, G.; Dessalvi, C. C.; Marino, P. N.; Di Ruocco, M. V.; Sartori, C.; Piccinino, C.; Parrinello, G.; Licata, G.; Torres, D.; Giambanco, S.; Busalacchi, S.; Arrotti, S.; Novo, S.; Inciardi, R. M.; Pieri, P.; Chirco, P. R.; Galifi, M. A.; Teresi, G.; Buccheri, D.; Minacapelli, A.; Veniani, M.; Frisinghelli, A.; Priori, S. G.; Cattaneo, S.; Opasich, C.; Gualco, A.; Pagliaro, M.; Mancone, M.; Fedele, F.; Cinque, A.; Vellini, M.; Scarfo, I.; Romeo, F.; Ferraiuolo, F.; Sergi, D.; Anselmi, M.; Melandri, F.; Leci, E.; Iori, E.; Bovolo, V.; Pidello, S.; Frea, S.; Bergerone, S.; Botta, M.; Canavosio, F. G.; Gaita, F.; Merlo, M.; Cinquetti, M.; Sinagra, G.; Ramani, F.; Fabris, E.; Stolfo, D.; Artico, J.; Miani, D.; Fresco, C.; Daneluzzi, C.; Proclemer, A.; Cicoira, M.; Zanolla, L.; Marchese, G.; Torelli, F.; Vassanelli, C.; Voronina, N.; Erglis, A.; Tamakauskas, V.; Smalinskas, V.; Karaliute, R.; Petraskiene, I.; Kazakauskaite, E.; Rumbinaite, E.; Kavoliuniene, A.; Vysniauskas, V.; Brazyte-Ramanauskiene, R.; Petraskiene, D.; Stankala, S.; Switala, P.; Juszczyk, Z.; Sinkiewicz, W.; Gilewski, W.; Pietrzak, J.; Orzel, T.; Kasztelowicz, P.; Kardaszewicz, P.; Lazorko-Piega, M.; Gabryel, J.; Mosakowska, K.; Bellwon, J.; Rynkiewicz, A.; Raczak, G.; Lewicka, E.; Dabrowska-Kugacka, A.; Bartkowiak, R.; Sosnowska-Pasiarska, B.; Wozakowska-Kaplon, B.; Krzeminski, A.; Zabojszcz, M.; Mirek-Bryniarska, E.; Grzegorzko, A.; Bury, K.; Nessler, J.; Zalewski, J.; Furman, A.; Broncel, M.; Poliwczak, A.; Bala, A.; Zycinski, P.; Rudzinska, M.; Jankowski, L.; Kasprzak, J. D.; Michalak, L.; Soska, K. W.; Drozdz, J.; Huziuk, I.; Retwinski, A.; Flis, P.; Weglarz, J.; Bodys, A.; Grajek, S.; Kaluzna-Oleksy, M.; Straburzynska-Migaj, E.; Dankowski, R.; Szymanowska, K.; Grabia, J.; Szyszka, A.; Nowicka, A.; Samcik, M.; Wolniewicz, L.; Baczynska, K.; Komorowska, K.; Poprawa, I.; Komorowska, E.; Sajnaga, D.; Zolbach, A.; Dudzik-Plocica, A.; Abdulkarim, A. -F.; Lauko-Rachocka, A.; Kaminski, L.; Kostka, A.; Cichy, A.; Ruszkowski, P.; Splawski, M.; Fitas, G.; Szymczyk, A.; Serwicka, A.; Fiega, A.; Zysko, D.; Krysiak, W.; Szabowski, S.; Skorek, E.; Pruszczyk, P.; Bienias, P.; Ciurzynski, M.; Welnicki, M.; Mamcarz, A.; Folga, A.; Zielinski, T.; Rywik, T.; Leszek, P.; Sobieszczanska-Malek, M.; Piotrowska, M.; Kozar-Kaminska, K.; Komuda, K.; Wisniewska, J.; Tarnowska, A.; Balsam, P.; Marchel, M.; Opolski, G.; Kaplon-Cieslicka, A.; Gil, R. J.; Mozenska, O.; Byczkowska, K.; Gil, K.; Pawlak, A.; Michalek, A.; Krzesinski, P.; Piotrowicz, K.; Uzieblo-Zyczkowska, B.; Stanczyk, A.; Skrobowski, A.; Ponikowski, P.; Jankowska, E.; Rozentryt, P.; Polonski, L.; Gadula-Gacek, E.; Nowalany-Kozielska, E.; Kuczaj, A.; Kalarus, Z.; Szulik, M.; Przybylska, K.; Klys, J.; Prokop-Lewicka, G.; Kleinrok, A.; Aguiar, C. T.; Ventosa, A.; Pereira, S.; Faria, R.; Chin, J.; De Jesus, I.; Santos, R.; Silva, P.; Moreno, N.; Queiros, C.; Lourenco, C.; Pereira, A.; Castro, A.; Andrade, A.; Guimaraes, T. O.; Martins, S.; Placido, R.; Lima, G.; Brito, D.; Francisco, A. R.; Cardiga, R.; Proenca, M.; Araujo, I.; Marques, F.; Fonseca, C.; Moura, B.; Leite, S.; Campelo, M.; Silva-Cardoso, J.; Rodrigues, J.; Rangel, I.; Martins, E.; Correia, A. S.; Peres, M.; Marta, L.; da Silva, G. F.; Severino, D.; Durao, D.; Leao, S.; Magalhaes, P.; Moreira, I.; Cordeiro, A. F.; Ferreira, C.; Araujo, C.; Ferreira, A.; Baptista, A.; Radoi, M.; Bicescu, G.; Vinereanu, D.; Sinescu, C. -J.; Macarie, C.; Popescu, R.; Daha, I.; Dan, G. -A.; Stanescu, C.; Dan, A.; Craiu, E.; Nechita, E.; Aursulesei, V.; Christodorescu, R.; Otasevic, P.; Seferovic, P. M.; Simeunovic, D.; Ristic, A. D.; Celic, V.; Pavlovic-Kleut, M.; Lazic, J. S.; Stojcevski, B.; Pencic, B.; Stevanovic, A.; Andric, A.; Iric-Cupic, V.; Jovic, M.; Davidovic, G.; Milanov, S.; Mitic, V.; Atanaskovic, V.; Antic, S.; Pavlovic, M.; Stanojevic, D.; Stoickov, V.; Ilic, S.; Ilic, M. D.; Petrovic, D.; Stojsic, S.; Kecojevic, S.; Dodic, S.; Adic, N. C.; Cankovic, M.; Stojiljkovic, J.; Mihajlovic, B.; Radin, A.; Radovanovic, S.; Krotin, M.; Klabnik, A.; Goncalvesova, E.; Pernicky, M.; Murin, J.; Kovar, F.; Kmec, J.; Semjanova, H.; Strasek, M.; Iskra, M. S.; Ravnikar, T.; Suligoj, N. C.; Komel, J.; Fras, Z.; Jug, B.; Glavic, T.; Losic, R.; Bombek, M.; Krajnc, I.; Krunic, B.; Horvat, S.; Kovac, D.; Rajtman, D.; Cencic, V.; Letonja, M.; Winkler, R.; Valentincic, M.; Melihen-Bartolic, C.; Bartolic, A.; Vrckovnik, M. P.; Kladnik, M.; Pusnik, C. S.; Marolt, A.; Klen, J.; Drnovsek, B.; Leskovar, B.; Anguita, M. J. F.; Page, J. C. G.; Martinez, F. M. S.; Andres, J.; Bayes-Genis, A.; Mirabet, S.; Mendez, A.; Garcia-Cosio, L.; Roig, E.; Leon, V.; Gonzalez-Costello, J.; Muntane, G.; Garay, A.; Alcade-Martinez, V.; Fernandez, S. L.; Rivera-Lopez, R.; Puga-Martinez, M.; Fernandez-Alvarez, M.; Serrano-Martinez, J. L.; Crespo-Leiro, M.; Grille-Cancela, Z.; Marzoa-Rivas, R.; Blanco-Canosa, P.; Paniagua-Martin, M. J.; Barge-Caballero, E.; Cerdena, I. L.; Baldomero, I. F. H.; Padron, A. L.; Rosillo, S. O.; Gonzalez-Gallarza, R. D.; Montanes, O. S.; Manjavacas, A. M. I.; Conde, A. C.; Araujo, A.; Soria, T.; Garcia-Pavia, P.; Gomez-Bueno, M.; Cobo-Marcos, M.; Alonso-Pulpon, L.; Cubero, J. S.; Sayago, I.; Gonzalez-Segovia, A.; Briceno, A.; Subias, P. E.; Hernandez, M. V.; Cano, M. J. R.; Sanchez, M. A. G.; Jimenez, J. F. D.; Garrido-Lestache, E. B.; Pinilla, J. M. G.; de la Villa, B. G.; Sahuquillo, A.; Marques, R. B.; Calvo, F. T.; Perez-Martinez, M. T.; Gracia-Rodenas, M. R.; Garrido-Bravo, I. P.; Pastor-Perez, F.; Pascual-Figal, D. A.; Molina, B. D.; Orus, J.; Gonzalo, F. E.; Bertomeu, V.; Valero, R.; Martinez-Abellan, R.; Quiles, J.; Rodrigez-Ortega, J. A.; Mateo, I.; Elamrani, A.; Fernandez-Vivancos, C.; Valero, D. B.; Almenar-Bonet, L.; Sanchez-Lazaro, I. J.; Marques-Sule, E.; Facila-Rubio, L.; Perez-Silvestre, J.; Garcia-Gonzalez, P.; Ridocci-Soriano, F.; Garcia-Escriva, D.; Pellicer-Cabo, A.; de la Fuente Galan, L.; Diaz, J. L.; Platero, A. R.; Arias, J. C.; Blasco-Peiro, T.; Julve, M. S.; Sanchez-Insa, E.; Aured-Guallar, C.; Portoles-Ocampo, A.; Melin, M.; Hagglund, E.; Stenberg, A.; Lindahl, I. -M.; Asserlund, B.; Olsson, L.; Dahlstrom, U.; Afzelius, M.; Karlstrom, P.; Tengvall, L.; Wiklund, P. -A.; Olsson, B.; Kalayci, S.; Temizhan, A.; Cavusoglu, Y.; Gencer, E.; Yilmaz, M. B.; Gunes, H