Water molecules as structural determinants among prions of low sequence identity

AbstractThe nature of the factors leading to the conversion of the cellular prion protein (PrPC) into its amyloidogenic isoform (PrPSc) is still matter of debate in the field of structural biology. The NMR structures of non-mammalian PrPC (non-mPrP) from frog, chicken and turtle [Calzolai, L., Lysek, D.A., Perez, D.R., Guntert, P. and Wuthrich, K. (2005) Prion protein NMR structures of chickens, turtles, and frogs. Proc. Natl. Acad. Sci. USA 102, 651–655] have provided some new and valuable information on the scaffolding elements that preserve the PrPC folding, despite their low sequence identity with the mammalian prions (mPrP). The present molecular dynamics study of non-mPrPC focuses on the hydration properties of these proteins in comparison with the mammalian ones. The data reveal new insights in the PrP hydration and focus on the implications for PrPC folding stability and its propensity for interactions. In addition, for the first time, a role in disfavoring the PrPC aggregation is suggested for a conserved β-bulge which is stabilized by the local hydration

LHCb online system, data acquisition and experiment control: Technical Design Report

none543P. R. Barbosa-Marinho;I. Bediaga;F. Barbosa-Ademarlaudo;G. Cernicchiaro;E. C. de;J. Magnin;J. M. de;A. Massafferri;A. Reis;R. Silva;S. Amato;P. Colrain;T. D. Silva;J. R. T;L. S. De;M. Gandelman;J. H. Lopes;B. Maréchal;D. Moraes;E. Polycarpo;F. V. do;Z. J. Ajaltouni;G. Böhner;V. Breton;R. Cornat;O. Deschamps;P. Henrard;J. Lecoq;P. Perret;C. Rimbault;C. Trouilleau;E. Aslanides;J. P. Cachemiche;P. Y. Duval;R. L. Gac;O. Leroy;P. L. Liotard;M. Menouni;R. Potheau;A. Y. Tsaregorodtsev;A. Y. Tsaregorodtsev;D. Boget;I. D. Bonis;D. Décamp;N. Dumont-Dayot;N. Fouque;M. Gourgerot;M. N. Minard;B. Pietrzyk;G. Barrand;C. Beigbeder-Beau;D. Breton;O. Callot;P. Cros;B. D'Almagne;B. Delcourt;F. Fulda-Quenzer;A. Jacholkowska;B. Jean-Marie;J. Lefrançois;F. P. Machefert;V. Tocut;K. D. Truong;R. Schwierz;B. Spaan;C. Bauer;D. Baumeister;N. Bulian;H. Fuchs;T. Glebe;W. Hofmann;K. T. Knöpfle;S. Löchner;A. Ludwig;F. Sánchez-Nieto;M. Schmelling;B. Schwingenheuer;S. Bachmann;P. Bock;H. Deppe;F. Eisele;M. Feuerstack-Raible;S. Henneberger;P. Igo-Kemenes;R. Rusnyak;U. Stange;U. Trunk;M. Walter;D. Wiedner;U. Uwer;V. Lindenstruth;R. Richter;M. W. Schulz;A. Walsch;G. Bencivenni;C. Bloise;F. Bossi;P. Campana;G. Capon;P. D. Simone;C. Forti;M. A. Franceschi;F. Murtas;L. Passalacqua;V. Patera;A. Sciubba;M. Bargiotti;A. Bertin;M. Bruschi;M. Capponi;I. D'Antone;S. D. Castro;P. Faccioli;L. Fabbri;D. Galli;B. Giacobbe;U. Marconi;I. Massa;M. Piccinini;M. Poli;N. Semprini-Cesari;R. Spighi;V. M. Vagnoni;S. Vecchi;M. Villa;A. Vitale;A. Zoccoli;S. Cadeddu;A. Cardini;M. Caria;A. Lai;D. Pinci;B. Saitta;V. Carassiti;A. Cotta-Ramusino;A. Gianoli;M. Martini;F. Petrucci;M. Savrié;A. Bizzeti;M. Calvetti;G. Collazuol;E. Iacopini;M. Lenti;F. Martelli;G. Passaleva;M. Veltri;S. Cuneo;F. Fontanelli;V. Gracco;P. Musico;A. Petrolini;M. Sannino;M. Alemi;T. Bellunato;M. Calvi;C. Matteuzzi;M. Musy;P. Negri;M. Paganoni;G. Auriemma;V. Bocci;V. Bosio;D. Fidanza;A. Frenkel;K. Harrison;G. Martellotti;S. Martínez;G. Penso;S. Petrarca;G. Pirozzi;R. Santacesaria;C. Satriano;A. Satta;G. Carboni;D. Dominici;G. Ganis;R. Messi;L. Pacciani;L. Paoluzi;E. Santovetti;G. v. Apeldoorn;N. V. Bakel;T. S. Bauer;J. F. J;H. J. Bulten;C. Cârloganu;M. Doets;R. V. der;I. Gouz;D. Groep;V. Gromov;R. Hierck;l. Hommels;E. Jans;T. Ketel;S. Klous;B. Köne;M. Merk;F. Mul;M. Needham;H. Schuijlenburg;T. Sluijk;J. V. Tilburg;H. D. Vries;L. Wiggers;M. Zupan;C. S. Gao;C. Jiang;H. Sun;Z. Zhu;M. Bisset;J. P. Cheng;Y. G. Cui;Y. Dai;Y. Gao;H. J. He;C. Huang;K. Y. Ping;Y. J. Li;Q. Li;Y. Liao;J. P. Ni;S. B. Bei;J. J. Su;Y. R. Tian;Q. Wang;Q. S. Yan;E. Banas;J. Blocki;K. Galuszka;L. Hajduk;P. Jalocha;P. Kapusta;B. Kisielewski;W. Kucewicz;T. Lesiak;J. Michalowski;B. Muryn;Z. Natkaniec;W. Ostrowicz;G. Polok;E. Rulikowska-Zarebska;M. Stodulski;T. Szumlak;M. Witek;P. Zychowski;M. Adamus;A. Chlopik;Z. Guzik;A. Nawrot;M. Szekowski;D. V. Anghel;C. Coca;A. Cimpean;G. Giolu;C. Magureanu;S. Popescu;T. Preda;A. M. Rosca;V. L. Rusu;V. N. Bolotov;S. N. Filippov;J. Gavrilov;E. Guschin;V. Kloubov;L. V. Kravchuk;S. Laptek;V. D. Laptev;V. Postoev;A. Sadovskii;I. N. Semeniouk;S. Barsuk;I. Belyaev;A. Golutvin;O. Gouchtchine;V. Kiritchenko;V. Kochetkov;I. Korolko;G. Pakhlova;N. Levitski;A. Morozov;P. Pakhlov;D. Roussinov;V. Y. Rusinov;S. V. Semenov;A. Soldatov;E. Tarkovski;K. I. Beloborodov;A. E. Bondar;A. Bozhenok;A. F. Buzulutskov;S. Eidelman;V. B. Golubev;P. P. Krokovnyi;S. B. Oreshkin;A. Poluektov;S. I. Serednyakov;L. I. Shekhtman;B. A. Shwartz;Z. K. Silagadze;A. Vasilev;L. A. Afanassieva;I. Ajinenko;K. S. Belous;V. Brekhovskikh;S. Denissov;A. V. Dorokhov;R. I. Dzhelyadin;A. Kobelev;A. K. Konoplyannikov;A. K. Likhoded;V. D. Matveev;V. Novikov;V. F. Obraztsov;A. P. Ostankov;V. I. Rykalin;V. K. Semenov;M. M. Shapkin;N. Smirnov;A. Sokolov;M. M. Soldatov;V. V. Talanov;O. P. Yushchenko;B. Botchine;S. Guetz;A. Kashchuk;V. A. Lazarev;N. Saguidova;V. Souvorov;E. M. Spiridenkov;A. Vorobyov;A. Vorobyov;E. Aguiló;R. Ballabriga;S. Ferragut;L. Garrido;D. Gascón;R. Graciani-Díaz;S. Luengo;R. Miquel;D. Peralta;M. Roselló;X. Vilasís;B. Adeva;P. Conde;F. Gómez;J. A. Hernando;A. Iglesias;A. López-Aguera;A. Pazos;M. Pló;J. M. Rodríguez;J. J. Saborido;M. J. Tobar;P. Bartalini;A. Bay;B. Carron;C. Currat;O. Dormond;F. Dürrenmatt;Y. Ermoline;R. Frei;G. Gagliardi;G. Haefeli;J. P. Hertig;P. Koppenburg;T. Nakada;J. Perroud;F. Ronga;O. Schneider;L. Studer;M. Tareb;M. T. Tran;R. Bernet;E. Holzschuh;F. Lehner;P. Sievers;O. Steinkamp;U. Straumann;A. Vollhardt;D. Wyler;M. Ziegler;A. Dovbnya;S. Maznichenko;O. Omelaenko;Y. Ranyuk;V. Shulayev;V. M. Aushev;V. Kiva;I. Kolomiets;Y. V. Pavlenko;V. Pugatch;Y. Vasilev;N. H. Brook;J. E. Cole;R. D. Head;A. Phillips;A. Presland;F. F. Wilson;K. George;V. Gibson;C. R. Jones;S. G. Katvars;C. H. Shepherd-Themistocleous;C. P. Ward;S. A. Wotton;C. A. J;C. J. Densham;S. Easo;B. J. Franek;J. G. V;R. Halsall;J. A. Lidbury;J. V. Morris;A. Papanestis;G. N. Patrick;F. J. P;S. A. Temple;M. L. Woodward;A. Barczyk;S. Eisenhardt;A. Khan;F. Muheim;S. Playfer;A. Walker;A. J. Flavell;A. Halley;V. O'Shea;A. Pickford;F. J. P;S. F. Biagi;T. J. V;R. Gamet;M. L. McCubbin;J. Palacios;C. Parkes;G. Patel;V. Wright;G. J. Barber;D. Clark;P. Dauncey;A. Duane;U. Egede;M. Girone;J. Hassard;R. Hill;M. J. J;S. Jolly;D. R. Price;P. Savage;L. W. Toudup;D. M. Websdale;M. Adinolfi;G. Damerell;J. Bibby;M. J. Charles;N. Harnew;F. Harris;I. C. McArthur;J. Rademacker;N. J. Smale;S. Topp-Jørgensen;G. R. Wilkinson;G. Anelli;F. Anghinolfi;F. Bal;M. Benayoun;R. Beneyton;W. Bonivento;A. Braem;J. Buytaert;M. Campbell;A. J. Cass;M. Cattaneo;P. Charpentier;E. G. Chesi;J. Christiansen;J. Closier;P. Collins;G. Corti;C. D'Ambrosio;H. Dijkstra;J. P. Dufey;M. Ferro-Luzzi;F. Fiedler;W. Flegel;F. Formenti;R. W. Forty;M. Frank;C. Frei;I. García-Alfonso;C. Gaspar;P. Gavillet;G. Gracía-Abríl;A. Guirao-Elias;T. Gys;F. Hahn;S. Haider;J. Harvey;B. Hay;E. V. Herwijnen;H. J. Hilke;G. V. Holtey;D. Hutchroft;R. Jacobsson;P. Jarron;C. Joram;B. Jost;D. Lacarrère;M. Laub;M. F. Letheren;J. Libby;C. Lippmann;R. Lindner;M. Losasso;P. Mato-Vila;H. Müller;N. Neufeld;K. Österberg;C. Padilla;U. Parzefall;S. Ponce;F. Ranjard;W. Riegler;F. Röhner;S. Roiser;T. Ruf;S. Schmeling;B. Schmidt;T. Schneider;A. Schopper;W. Snoeys;W. Tejessy;F. Teubert;J. F. Toledo-Alarcón;O. Ullaland;A. Valassi;P. Vázquez-Regueiro;I. Videau;P. Wertelaers;A. Wright;K. WyllieBarbosa Marinho, P. R.; Bediaga, I.; Barbosa Ademarlaudo, F.; Cernicchiaro, G.; E. C., De; Magnin, J.; J. M., De; Massafferri, A.; Reis, A.; Silva, R.; Amato, S.; Colrain, P.; Silva, T. D.; J. R., T; L. S., De; Gandelman, M.; Lopes, J. H.; Maréchal, B.; Moraes, D.; Polycarpo, E.; F. V., Do; Ajaltouni, Z. J.; Böhner, G.; Breton, V.; Cornat, R.; Deschamps, O.; Henrard, P.; Lecoq, J.; Perret, P.; Rimbault, C.; Trouilleau, C.; Aslanides, E.; Cachemiche, J. P.; Duval, P. Y.; Gac, R. L.; Leroy, O.; Liotard, P. L.; Menouni, M.; Potheau, R.; Tsaregorodtsev, A. Y.; Tsaregorodtsev, A. Y.; Boget, D.; Bonis, I. D.; Décamp, D.; Dumont Dayot, N.; Fouque, N.; Gourgerot, M.; Minard, M. N.; Pietrzyk, B.; Barrand, G.; Beigbeder Beau, C.; Breton, D.; Callot, O.; Cros, P.; D'Almagne, B.; Delcourt, B.; Fulda Quenzer, F.; Jacholkowska, A.; Jean Marie, B.; Lefrançois, J.; Machefert, F. P.; Tocut, V.; Truong, K. D.; Schwierz, R.; Spaan, B.; Bauer, C.; Baumeister, D.; Bulian, N.; Fuchs, H.; Glebe, T.; Hofmann, W.; Knöpfle, K. T.; Löchner, S.; Ludwig, A.; Sánchez Nieto, F.; Schmelling, M.; Schwingenheuer, B.; Bachmann, S.; Bock, P.; Deppe, H.; Eisele, F.; Feuerstack Raible, M.; Henneberger, S.; Igo Kemenes, P.; Rusnyak, R.; Stange, U.; Trunk, U.; Walter, M.; Wiedner, D.; Uwer, U.; Lindenstruth, V.; Richter, R.; Schulz, M. W.; Walsch, A.; Bencivenni, G.; Bloise, C.; Bossi, F.; Campana, P.; Capon, G.; Simone, P. D.; Forti, C.; Franceschi, M. A.; Murtas, F.; Passalacqua, L.; Patera, V.; Sciubba, A.; Bargiotti, M.; Bertin, A.; Bruschi, M.; Capponi, M.; D'Antone, I.; Castro, S. D.; Faccioli, P.; Fabbri, L.; Galli, D.; Giacobbe, B.; Marconi, U.; Massa, I.; Piccinini, M.; Poli, M.; Semprini Cesari, N.; Spighi, R.; Vagnoni, V. M.; Vecchi, S.; Villa, M.; Vitale, A.; Zoccoli, A.; Cadeddu, S.; Cardini, A.; Caria, M.; Lai, A.; Pinci, D.; Saitta, B.; Carassiti, V.; Cotta Ramusino, A.; Gianoli, A.; Martini, M.; Petrucci, F.; Savrié, M.; Bizzeti, A.; Calvetti, M.; Collazuol, G.; Iacopini, E.; Lenti, M.; Martelli, F.; Passaleva, G.; Veltri, M.; Cuneo, S.; Fontanelli, Flavio; Gracco, V.; Musico, P.; Petrolini, Alessandro; Sannino, M.; Alemi, M.; Bellunato, T.; Calvi, M.; Matteuzzi, C.; Musy, M.; Negri, P.; Paganoni, M.; Auriemma, G.; Bocci, V.; Bosio, V.; Fidanza, D.; Frenkel, A.; Harrison, K.; Martellotti, G.; Martínez, S.; Penso, G.; Petrarca, S.; Pirozzi, G.; Santacesaria, R.; Satriano, C.; Satta, A.; Carboni, G.; Dominici, D.; Ganis, G.; Messi, R.; Pacciani, L.; Paoluzi, L.; Santovetti, E.; Apeldoorn, G. v.; Bakel, N. V.; Bauer, T. S.; J. F., J; Bulten, H. J.; Cârloganu, C.; Doets, M.; Der, R. V.; Gouz, I.; Groep, D.; Gromov, V.; Hierck, R.; Hommels, L.; Jans, E.; Ketel, T.; Klous, S.; Köne, B.; Merk, M.; Mul, F.; Needham, M.; Schuijlenburg, H.; Sluijk, T.; Tilburg, J. V.; Vries, H. D.; Wiggers, L.; Zupan, M.; Gao, C. S.; Jiang, C.; Sun, H.; Zhu, Z.; Bisset, M.; Cheng, J. P.; Cui, Y. G.; Dai, Y.; Gao, Y.; H. J., He; Huang, C.; Ping, K. Y.; Y. J., Li; Li, Q.; Liao, Y.; J. P., Ni; Bei, S. B.; J. J., Su; Tian, Y. R.; Wang, Q.; Yan, Q. S.; Banas, E.; Blocki, J.; Galuszka, K.; Hajduk, L.; Jalocha, P.; Kapusta, P.; Kisielewski, B.; Kucewicz, W.; Lesiak, T.; Michalowski, J.; Muryn, B.; Natkaniec, Z.; Ostrowicz, W.; Polok, G.; Rulikowska Zarebska, E.; Stodulski, M.; Szumlak, T.; Witek, M.; Zychowski, P.; Adamus, M.; Chlopik, A.; Guzik, Z.; Nawrot, A.; Szekowski, M.; Anghel, D. V.; Coca, C.; Cimpean, A.; Giolu, G.; Magureanu, C.; Popescu, S.; Preda, T.; Rosca, A. M.; Rusu, V. L.; Bolotov, V. N.; Filippov, S. N.; Gavrilov, J.; Guschin, E.; Kloubov, V.; Kravchuk, L. V.; Laptek, S.; Laptev, V. D.; Postoev, V.; Sadovskii, A.; Semeniouk, I. N.; Barsuk, S.; Belyaev, I.; Golutvin, A.; Gouchtchine, O.; Kiritchenko, V.; Kochetkov, V.; Korolko, I.; Pakhlova, G.; Levitski, N.; Morozov, A.; Pakhlov, P.; Roussinov, D.; Rusinov, V. Y.; Semenov, S. V.; Soldatov, A.; Tarkovski, E.; Beloborodov, K. I.; Bondar, A. E.; Bozhenok, A.; Buzulutskov, A. F.; Eidelman, S.; Golubev, V. B.; Krokovnyi, P. P.; Oreshkin, S. B.; Poluektov, A.; Serednyakov, S. I.; Shekhtman, L. I.; Shwartz, B. A.; Silagadze, Z. K.; Vasilev, A.; Afanassieva, L. A.; Ajinenko, I.; Belous, K. S.; Brekhovskikh, V.; Denissov, S.; Dorokhov, A. V.; Dzhelyadin, R. I.; Kobelev, A.; Konoplyannikov, A. K.; Likhoded, A. K.; Matveev, V. D.; Novikov, V.; Obraztsov, V. F.; Ostankov, A. P.; Rykalin, V. I.; Semenov, V. K.; Shapkin, M. M.; Smirnov, N.; Sokolov, A.; Soldatov, M. M.; Talanov, V. V.; Yushchenko, O. P.; Botchine, B.; Guetz, S.; Kashchuk, A.; Lazarev, V. A.; Saguidova, N.; Souvorov, V.; Spiridenkov, E. M.; Vorobyov, A.; Vorobyov, A.; Aguiló, E.; Ballabriga, R.; Ferragut, S.; Garrido, L.; Gascón, D.; Graciani Díaz, R.; Luengo, S.; Miquel, R.; Peralta, D.; Roselló, M.; Vilasís, X.; Adeva, B.; Conde, P.; Gómez, F.; Hernando, J. A.; Iglesias, A.; López Aguera, A.; Pazos, A.; Pló, M.; Rodríguez, J. M.; Saborido, J. J.; Tobar, M. J.; Bartalini, P.; Bay, A.; Carron, B.; Currat, C.; Dormond, O.; Dürrenmatt, F.; Ermoline, Y.; Frei, R.; Gagliardi, G.; Haefeli, G.; Hertig, J. P.; Koppenburg, P.; Nakada, T.; Perroud, J.; Ronga, F.; Schneider, O.; Studer, L.; Tareb, M.; Tran, M. T.; Bernet, R.; Holzschuh, E.; Lehner, F.; Sievers, P.; Steinkamp, O.; Straumann, U.; Vollhardt, A.; Wyler, D.; Ziegler, M.; Dovbnya, A.; Maznichenko, S.; Omelaenko, O.; Ranyuk, Y.; Shulayev, V.; Aushev, V. M.; Kiva, V.; Kolomiets, I.; Pavlenko, Y. V.; Pugatch, V.; Vasilev, Y.; Brook, N. H.; Cole, J. E.; Head, R. D.; Phillips, A.; Presland, A.; Wilson, F. F.; George, K.; Gibson, V.; Jones, C. R.; Katvars, S. G.; Shepherd Themistocleous, C. H.; Ward, C. P.; Wotton, S. A.; C. A., J; Densham, C. J.; Easo, S.; Franek, B. J.; J. G., V; Halsall, R.; Lidbury, J. A.; Morris, J. V.; Papanestis, A.; Patrick, G. N.; F. J., P; Temple, S. A.; Woodward, M. L.; Barczyk, A.; Eisenhardt, S.; Khan, A.; Muheim, F.; Playfer, S.; Walker, A.; Flavell, A. J.; Halley, A.; O'Shea, V.; Pickford, A.; F. J., P; Biagi, S. F.; T. J., V; Gamet, R.; Mccubbin, M. L.; Palacios, J.; Parkes, C.; Patel, G.; Wright, V.; Barber, G. J.; Clark, D.; Dauncey, P.; Duane, A.; Egede, U.; Girone, M.; Hassard, J.; Hill, R.; M. J., J; Jolly, S.; Price, D. R.; Savage, P.; Toudup, L. W.; Websdale, D. M.; Adinolfi, M.; Damerell, G.; Bibby, J.; Charles, M. J.; Harnew, N.; Harris, F.; Mcarthur, I. C.; Rademacker, J.; Smale, N. J.; Topp Jørgensen, S.; Wilkinson, G. R.; Anelli, G.; Anghinolfi, F.; Bal, F.; Benayoun, M.; Beneyton, R.; Bonivento, W.; Braem, A.; Buytaert, J.; Campbell, M.; Cass, A. J.; Cattaneo, M.; Charpentier, P.; Chesi, E. G.; Christiansen, J.; Closier, J.; Collins, P.; Corti, G.; D'Ambrosio, C.; Dijkstra, H.; Dufey, J. P.; Ferro Luzzi, M.; Fiedler, F.; Flegel, W.; Formenti, F.; Forty, R. W.; Frank, M.; Frei, C.; García Alfonso, I.; Gaspar, C.; Gavillet, P.; Gracía Abríl, G.; Guirao Elias, A.; Gys, T.; Hahn, F.; Haider, S.; Harvey, J.; Hay, B.; Herwijnen, E. V.; Hilke, H. J.; Holtey, G. V.; Hutchroft, D.; Jacobsson, R.; Jarron, P.; Joram, C.; Jost, B.; Lacarrère, D.; Laub, M.; Letheren, M. F.; Libby, J.; Lippmann, C.; Lindner, R.; Losasso, M.; Mato Vila, P.; Müller, H.; Neufeld, N.; Österberg, K.; Padilla, C.; Parzefall, U.; Ponce, S.; Ranjard, F.; Riegler, W.; Röhner, F.; Roiser, S.; Ruf, T.; Schmeling, S.; Schmidt, B.; Schneider, T.; Schopper, A.; Snoeys, W.; Tejessy, W.; Teubert, F.; Toledo Alarcón, J. F.; Ullaland, O.; Valassi, A.; Vázquez Regueiro, P.; Videau, I.; Wertelaers, P.; Wright, A.; Wyllie, K

Health-status outcomes with invasive or conservative care in coronary disease

BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used

Ezetimibe added to statin therapy after acute coronary syndromes

BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization ( 6530 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P = 0.016). Rates of pre-specified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit