3,827 results on '"Scott RS"'
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2. Relationship of low molecular weight fluorophore levels with clinical factors and fenofibrate effects in adults with type 2 diabetes
- Author
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Januszewski, AS, Chen, D, Scott, RS, O'Connell, RL, Aryal, NR, Sullivan, DR, Watts, GF, Taskinen, M-R, Barter, PJ, Best, JD, Simes, RJ, Keech, AC, Jenkins, AJ, Januszewski, AS, Chen, D, Scott, RS, O'Connell, RL, Aryal, NR, Sullivan, DR, Watts, GF, Taskinen, M-R, Barter, PJ, Best, JD, Simes, RJ, Keech, AC, and Jenkins, AJ
- Abstract
People with diabetes are at risk of chronic complications and novel biomarkers, such as Advanced glycation end-products (AGEs) may help stratify this risk. We assessed whether plasma low-molecular weight AGEs, also known as LMW-fluorophores (LMW-F), are associated with risk factors, predict complications, and are altered by fenofibrate in adults with type 2 diabetes. Plasma LMW-F were quantified at baseline, after six weeks fenofibrate, and one year post-randomisation to fenofibrate or placebo. LMW-F associations with existing and new composite vascular complications were determined, and effects of fenofibrate assessed. LMW-F correlated positively with age, glycated haemoglobin (HbA1c), pulse pressure, kidney dysfunction and inflammation; and negatively with urate, body mass index, oxidative stress and leptin, albeit weakly (r = 0.04-0.16, all p < 0.01). Independent determinants of LMW-F included smoking, diastolic blood pressure, prior cardiovascular disease or microvascular complications, Caucasian ethnicity, kidney function, HbA1c and diabetes duration (all p ≤ 0.01). Baseline LMW-F tertiles correlated with on-trial macrovascular and microvascular complications (trend p < 0.001) on univariate analyses only. Six weeks of fenofibrate increased LMW-F levels by 21% (p < 0.001). In conclusion, LMW-F levels correlate with many risk factors and chronic diabetes complications, and are increased with fenofibrate. LMW-F tertiles predict complications, but not independently of traditional risk factors.
- Published
- 2021
3. The relationship of neutrophil elastase and proteinase 3 with risk factors, and chronic complications in type 2 diabetes: A Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) sub-study
- Author
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Ong, K-L, Wu, L, Januszewski, AS, O'Connell, R, Xu, A, Scott, RS, Sullivan, DR, Rye, K-A, Li, H, Ma, RCW, Li, L, Gebski, V, Jenkins, AJ, Jia, W, Keech, AC, Ong, K-L, Wu, L, Januszewski, AS, O'Connell, R, Xu, A, Scott, RS, Sullivan, DR, Rye, K-A, Li, H, Ma, RCW, Li, L, Gebski, V, Jenkins, AJ, Jia, W, and Keech, AC
- Abstract
INTRODUCTION: Neutrophil elastase (NE) and proteinase 3 (PR3) are novel inflammation biomarkers. We investigated their associations with chronic complications, determinants of biomarker levels and effects of fenofibrate in patients with type 2 diabetes mellitus (T2DM) from Fenofibrate Intervention and Event Lowering in Diabetes study. METHODS: Plasma NE and PR3 levels were quantified at baseline (n = 2000), and relationships with complications over 5-years assessed. Effects of fenofibrate on biomarker levels (n = 200) were determined at four follow-up visits. RESULTS: Higher waist-to-hip ratio, homocysteine and C-reactive protein and lower apoA-II were determinants of higher NE and PR3 levels. Higher NE levels were associated with on-trial stroke and cardiovascular mortality, and higher PR3 levels with on-trial stroke, but associations were not significant after adjustment for confounding factors. Although higher NE and PR3 levels were associated with baseline total microvascular disease, only NE levels were associated with on-trial neuropathy or amputation. These associations were not significant after adjusting for multiple comparisons. NE and PR3 levels did not change with fenofibrate. CONCLUSIONS: In T2DM plasma NE and PR3 levels are associated with vascular risk factors, and total microvascular disease at baseline, but on rigorous analyses were not associated with on-trial complications. Levels were not changed by fenofibrate.
- Published
- 2021
4. Diabetes Mellitus Incidence in Growth Hormone Treated Patients: Experience from the Global GeNeSIS Observational Program.
- Author
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Child, CJ, primary, Scott, RS, additional, Zimmermann, AG, additional, and Blum, WF, additional
- Published
- 2010
- Full Text
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5. Comparison of indices of insulin resistance with metabolic syndrome classifications to predict the development of impaired fasting glucose in overweight and obese subjects: a 3-year prospective study
- Author
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Shand, BI, Scott, RS, Lewis, JG, Elder, PA, and Frampton, CM
- Published
- 2009
- Full Text
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6. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients
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Ridker, P. M., Revkin, J., Amarenco, P., Brunell, R., Civeira, F., Flather, M., Glynn, R. J., Gregoire, J., Jukema, J. W., Karpov, Y., Kastelein, J. J. P., Koenig, W., Lorenzatti, A., Manga, P., Masiukiewicz, U., Miller, M., Mosterd, A., Murin, J., Nicolau, J. C., Nissen, S., Ponikowski, P., Santos, R. D., Schwartz, P. F., Soran, H., White, H., Wright, R. S., Vrablik, M., Yunis, C., Shear, C. L., Tardif, Conde D, J. -C., Colquhoun, D, Missault, L, Grégoire, J, Gao, R, Urina, M, Solar, M, Jensen, Hk, Grobbee, D, Savolainen, M, Schiele, Fn, Montalescot, G, Edes, I, Blake, G, Lotan, C, Maggioni, A, Savonitto, S, Lee, Cw, Leiva Pons JL, Dan, Ga, Cortada, Jb, Mellbin, L, Kahan, T, Noble, S, Hwang, Jj, Sritara, P, Tökgozoğlu, L, Tarasenko, L, Borer, Js, Black, H, Carmena, R, Furie, Kl, Mcmurray, J, Neaton, J, Zannad, F, O’Neill, B, Welty, F, Mcnamara, R, Chun, H, Abbott, Jd, Jacoby, D, Mcpherson, C, Jadbabaie, F, Pinto, D, Mccullough, L, Silverman, Ie, Sansing, Lh, Dearborn-Tomazos, J, Foody, J, Schindler, J, Piazza, G, Chakrabarti, A, Pride, Y, Gelfand, E, Baultrukonis, D, Chaudhuri, S, Frederich, R, Johnson, M, Mridha, K, Powell, C, Wang, E, Wei, C, Anderson, P, Buonanno, M, Epsley, C, Evans, B, Frolova, M, Goetsch, M, Hessinger, D, Ikehara, E, Ivanac, K, Kizko, J, Le, K, McNally-Dufort, C, Morocco, T, Nadkarni, S, Nissen, T, Nye, R, Pak, R, Pence, D, Redifer, P, Schwartz, W, Sattler, C, Schade, R, Sullivan, B, Wegner, J, Alvarez, Ca, Budassi, N, Vogel, Dr, Avaca, H, Conde, Dg, Estol, Cc, Gelersztein, E, Glenny, Ja, Hershson, Ar, Bruno, Rl, Maffei, Le, Soler, Jm, Zaidman, Cj, Carnero, Gs, Colombo, Hr, Jure, Ho, Luquez, Ha, Ramos, Hr, Resk, Jh, Rusculleda, Mm, Ulla, Mr, Caccavo, A, Farias, Ef, Wenetz, Lm, Cabella, Pr, Cuadrado, Ja, Chahin, M, Mackinnon, Ij, Zarandon, Rb, Schmidberg, J, Fernandez, Aa, Montana, O, Codutti, Or, Gorosito, Vm, Maldonado, N, Sala, J, De La Fuente RA, Casabella, Te, Di Gennaro JP, Guerrero, Ra, Alvarez, Ms, Berli, M, Botta, Ce, Montenegro, Ee, Vico, Ml, Begg, A, Lehman, R, Gilfillan, Cp, D'Emden, M, Markovic, Tp, Sullivan, D, Aroney, C, Stranks, Sn, Crimmins, Ds, Arstall, M, Van Gaal, W, Davis, T, Aylward, Pe, Amerena, J, William, M, Proietto, J, Purnell, Pw, Singh, B, Arya, Kw, Dart, Am, Thompson, P, Davis, Sm, Carroll, Pa, De Looze, F, Jayasinghe, R, Bhindi, R, Buysschaert, I, Sarens, T, van de Borne, P, Scott, Bp, Roosen, J, Cools, F, Missault, Lh, Debroye, C, Schoors, Df, Hollanders, G, Schroe, Hh, De Sutter, J, Hermans, K, Carlier, M, van Landegem, P, Verwerft, J, Mulleners, T, Delforge, Md, Soufflet, V, Elegeert, I, Descamps, Os, Janssens, S, Lemmens, Rc, Desfontaines, P, Scheen, A, Heijmans, S, Capiau, L, Vervoort, G, Carlier, Sg, Faes, D, Alzand, B, Keuleers, S, De Wolf, L, Thoeng, J, De Bruyne, L, de Santos MO, Felicio, Js, Areas, Ca, Figueiredo, El, Michalaros, Yl, Neuenschwander, Fc, Reis, G, Saad, Ja, Kormann, Ap, Nascimento, Cv, Precoma, Db, Abib, E Jr, dos Santos FR, Mello, Yg, Saraiva, Jf, Rech, Rl, Cerci, R, Fortes, Ja, Rossi, Pr, de Lima, e Silva FA, Hissa, M, Silva, Rp, de Souza WK, Guimarães Filho FV, Mangili, Oc, de Oliveira Paiva MS, Tumelero, R, Abrantes, Ja, Caramori, Pr, Dutra, Op, Leaes, Pe, Manenti, Er, Polanczyk, Ca, Bandeira, e Farias FA, de Moraes Junior JB, Russo, La, Alves AR Jr, Dracoulakis, Md, Ritt, Le, Saporito, Wf, Herdy, Ah, Maia, Ln, Sternieri, Mv, Ayoub, Jc, Bianco, Ht, da Costa FA, Eliaschewitz, Fg, Fonseca, Fa, Nakandakare, Er, Bonansea, Tc, Castro, Nm, de Barros, e Silva PG, Smith, P, Botelho, Rv, Resende, Es, Barbieri, Ds, Hernandes, Me, Bajaj, H, Beaudry, P, Berlingieri, Jc, Salter, Tj, Ajala, B, Anderson, Tj, Nanji, A, Ross, S, Pandey, S, Desrosiers, D, Gaudet, D, Moran, G, Csanadi, Ma, St-Amour, E, Cusimano, S, Halperin, Fa, Babapulle, M, Vizel, S, Petrella, J, Spence, Jd, Gupta, N, Tellier, G, Bourgeois, R, Gregóire, Jc, Wesson, T, Zadra, R, Twum-Barima, Dy, Cha, Jy, Hartleib, Mc, Bergeron, J, Chouinard, G, Mcpherson, Tp, Searles, G, Peterson, Sr, Mukherjee, A, Lepage, S, Conway, Jr, Kouz, Sm, Dion, D, Pesant, Y, Cheung, Ss, Goldenberg, Rm, Aronson, R, Gupta, Ak, O’Mahoney, M, Pliamm, L, Teitelbaum, I, Hoag, Gn, Nadra, Ij, Yared, Z, Yao, Lc, Nguyen, T, Saunders, Kk, Potthoff, S, Varleta, P, Assef, V, Godoy, Jg, Olivares, C, Roman, O, Vejar, M, Montecinos, H, Pincetti, C, Li, Y, Wang, D, Li, J, Yang, X, Du, Y, Wang, G, Yang, P, Zhang, X, Xu, P, Zhao, Y, Chen, J, Li, S, Li, W, Zhang, L, Zhu, Y, Zhang, Y, Zhou, C, Wang, Y, Liu, F, Ma, Y, Ti, Z, Zeng, X, Zhou, Y, Cui, G, Li, D, Xue, L, Jiang, J, Lian, Y, He, Y, Mendoza, Ja, Bonfanti, Ja, Dada, Fa, Urina-Triana, Ma, Rodriguez, Wr, Sanchez, Ml, Lozno, Hy, Triana, Eh, Arambula, Rm, Rico-Carrillo, Ae, Gallo, Hj, Catano, Js, Jattin, Fg, Plazas, Ja, Gomez, Je, Botero-Lopez, R, Gomez, Ni, Munoz, Cf, Pelaez, Sv, Eraso, Am, Goyes, Ar, Elbl, L, Fiserova, N, Vesely, J, Wasserburger, B, Blaha, V, Vojacek, J, Maskova, P, Hutyra, M, Vrkoc, J, Hala, T, Vodnansky, P, Bocek, P, Cifkova, R, Bufka, V, Ceska, R, Machkova, M, Zidkova, E, Lukac, M, Mikusova, T, Kellnerova, I, Kuchar, L, Ferkl, R, Cech, V, Zemek, S, Monhart, Z, Davidsen, F, Joensen, A, Lihn, As, Rasmussen, Tk, Wiggers, H, Lindgren, Lm, Schmidt, U, Galatius, S, Sillesen, H, Bronnum Schou, J, Thomsen, Kk, Urhammer, S, Jeppensen, J, Schou, M, May, O, Steffensen, R, Nielsen, Wb, Nielesen, T, Jepsen, Jm, Rai, A, Sykulski, R, Andersen, Lt, Rickers, H, Frost, L, Lomholdt, J, Egstrup, K, Wermuth, S, Klausen, L, Lassus, J, Palomaki, A, Khari, J, Tatlisumak, T, Kekki, S, Vanttinen, E, Strandberg, A, Valtonen, M, Sia, Sm, Nerg, O, Puhakka, M, Strand, J, Timonen, M, Levola, J, Arstila, L, Taurio, J, Kantola, I, Suomi, J, Humaloja, K, Askonen, K, Schiele, F, Sibon, I, Zemour, G, Goube, P, Petit, C, Chati, Z, Range, G, Rabahi, F, Rihani, R, Bergerot, C, Roubille, F, Boye, A, Probst, V, Ferrari, E, Cayla, G, Thouvenot, E, Delarche, N, Couffinhal, T, Coisne, D, Paillard, F, Elbaz, M, Decoulx, E, Angoulvant, D, Agraou, B, Caudmont, S, Berrouschot, J, Lauer, B, Schoell, I, Trenk, D, Derwahl, Km, Khariouzov, A, Proepper, F, Stawowy, P, Da Stephan, U, Stoessel, J, Voehringer, Hf, Dorsel, T, Stellbrink, C, Rinke, A, Northroff, J, Bourhaial, H, Stratmann, M, Wetzel, T, Axthelm, C, Guenzel, A, Weigmann, I, Faghih, M, Hagemann, D, Schaefer, A, Weber, D, Luedemann, J, Contzen, C, Kornmann, Mo, Winkelmann, B, Simon, J, Felix, S, Brauer, C, Laufs, U, Schmidt, E, Marten, I, Licka, M, Heisters, J, Appel, Kf, Kleinecke-Pohl, U, Klein, C, von Hodenberg EF, Maus, O, Sigal, H, Taeschner, H, Schwimmbeck, P, Lemke, B, Perings, C, Illies, G, Pfuetzner, A, Salbach, P, Hengstenberg, C, Kohler, A, Mudra, H, Behnke, T, Baar, M, Jeserich, M, Scholz, G, Naudts, I, Voller, H, Herrmann, Hj, von Engelhardt CB, Gerke, S, Pohlmeier, L, Schaufele, T, Woehrle, J, Al-Zoebi, A, Horacek, T, Peterfai, E, Kemeny, V, Lakatos, F, Bod, E, Andrassy, P, Andreka, P, Balo, T, Davidovits, Z, Laszlo, Z, Nagy, K, Papp, A, Somogyi, A, Toldy-Schedel, E, Vertes, A, Voros, P, Paragh, G, Martyin, T, Hajdu, C, Deak, L, Farago, K, Nagy, A, Kirschner, R, Koszegi, Z, Zilahi, Z, Toth, K, Wittmann, I, Bajcsi, D, Reiber, I, Toth, L, Benczur, B, Nagy, L, Sydo, T, Lupkovics, G, Oroszlan, T, Crean, P, Mahon, Ng, Mcadam, B, Macneill, B, Katz, A, Tsalihin, D, Vazan, A, Eitan, A, Lewis, Bs, Gavish, D, Wainstein, J, Mosenzon, O, Mosseri, M, Vishlitzky, V, Atar, S, Nseir, Wb, Brenner, H, Elis, A, Fuchs, S, Shimon, I, Solodky, A, Goldhaber, A, Tanne, D, Knobler, H, Kracoff, Oh, Hussein, O, Auriel, E, Chorin, E, Sharir, T, Bitzur, R, Shechter, M, Antonicelli, R, Franceschini, E, Porcu, M, Sesti, G, Maggiolini, S, Salvioni, A, Filardi, Pp, Trimarco, B, Averna, M, Pasqualini, L, Pirro, M, Pantaleoni, M, Piovaccari, G, Arca, M, Fedele, Francesco, Roncon, L, Anselmi, M, Sganzerla, P, Morocutti, G, Bonora, E, Dimas, Al, Esperon, Ga, Morales-Villegas, E, Isunza, Jm, Beltran, Lg, Molina, Ca, Garcia, Dk, Ruiz, La, Reyna, Ls, De los Rios Ibarra MO, Soto, Jr, Gonzalez-Ortiz, M, Herrera-Marmolejo, M, Ramos, Sa, Ramos-Lopez, Ga, Stobschinski, Ca, Aguilarsalinas, Ca, Alpizar-Salazar, M, Jimenez-Sanchez, M, Sanchez Mijangos JH, Elizondo Moreno ER, Garcia Castillo, A, Garcia Hernandez PA, Gonzalez-Gonzalez, Jg, Riojas Charles CM, Valdez Lopez HG, Nuriulu Escobar PL, Lechuga Martin del Campo, A, Castro Montes BE, Mendez Bucio, A, Rodriguez-Briones, I, Torre Amione, G, Violante Ortiz, R, Luna Ceballos RI, Lopez Rosas, E, Bax, Wa, Alhakim, M, van de Wiel, A, Liem, Ss, Groutars, Rg, Herrman, Jp, Hovingh, Gk, van de Wetering ML, van Royen, N, Groenemeijer, Be, Hoedemaker, G, Schaap, J, Ronner, E, Angun, M, Mairuhu, At, Van Alem AP, Martens, Fm, Heijmeriks, Ja, van Hal JM, Schoofs, Mw, den Hartog FR, Kentgens, S, Post, Jc, Louwerenburg, Jw, van Rossum, P, Viergever, Ep, Donders, Sh, Kamphuisen, Pw, van Beek, E, Nijmeijer, R, Lenderink, T, Schreuder, T, Kuijper, Af, The, Sh, Van het Hof-Wiersma JJ, Tichelaar, P, Westerndorp, I, Breedveld, Rw, Karalis, I, Romer, Tj, Bogaard, K, Van Koningsbruggen, P, Kroon, Aa, Hoogslag, Pa, Rensing, Bj, Cramer, E, Remmen, Jj, Riksen, Np, Bokern, Mj, Cabezas, Mc, Mulder, H, Nierop, Pr, van Kempen WW, Zoet-Nugteren, Sk, van Daele ME, Swart, Hp, van der Zwaan CT, Hermans, Wr, Magro, M, van de Wal RM, Hassink, Rj, Visseren, F, Veenendaal, A, De Nooijer, C, Troquay, Rp, Imholz, Bp, van der Meer, P, Visser, Rp, van Leendert RJ, Gosselink, Ma, Baker, J, Benatar, Jr, Kerr, J, Pryke, Jr, Scott, Rs, Millar-Corte, Gd, Williams, M, Montgomery, B, Venter, Dj, Ternouth, If, Decaigney, Sc, Hart, Hh, Corin, A, Garden, Pi, Sheahan, D, Harding, Sa, Korecki, J, Supronik, J, Styczkiewicz, M, Bijata-Bronisz, R, Rusicka, T, Walczak, M, Krolikowski, Z, Ostrowski, J, Lukaszewicz, M, Przekwas-Jaruchowska, M, Zieba, B, Miekus, P, Orkwiszewska-Nalewajko, A, Piepiorka, M, Kubalski, P, Wychota, K, Blach, E, Ochala, A, Okopien, B, Wronska, D, Janion, M, Czarnecka, D, Kolodziejczyk, J, Konieczynska, M, Landa, K, Mirek-Bryniarska, E, Necki, M, Pasternak, Da, Rozpondek, P, Trebacz, J, Walczewska, J, Sidor, M, Broncel, M, Drozdz, J, Kosmider, M, Saryusz-Wolska, M, Kucharska, D, Opalinska, E, Pijanowski, Z, Wozniak, I, Banaszkiewicz, K, Klecha, A, Horodecki, M, Piskorz-Wapinska, J, Kobielusz-Gembala, I, Kim, Mh, Kim, Dk, Cho, Br, Kim, Ks, Her, Sh, Lee, Sy, Rhee, My, Kim, K, Kang, Wc, Kim, Dh, Cho, Ys, Kim, Sh, Rim, Sj, Tahk, Sj, Jeon, Hk, Yoon, J, Mociran, M, Pop, Cf, Minescu, B, Andrei, Ld, Radoi, M, Calin, A, Ciomag, Rm, Copaci, I, Fruntelata, Ag, Popescu, M, Tivadar, S, Roman, G, Avram, Ri, Mistodie, Cv, Morosanu, M, Popa, Ar, Popescu, Ml, Popoviciu, Ms, Tase, A, Busegeanu, M, Popescu, A, Szilagyi, I, Sitterli-Natea, Cn, Maximov, Dm, Munteanu, M, Negrisanu, Gd, Kuzin, A, Popov, D, Shapovalova, J, Vishneva, E, Shutemova, E, Pasechnik, E, Bogdanov, E, Khasanov, N, Barbarash, Ol, Shangina, Oa, Tarasov, N, Solonev, O, Kosmacheva, E, Chernyatina, Ma, Ginzburg, M, Blokhin, A, Bulanova, N, Drapkina, Om, Gordeev, Ig, Libov, Ia, Lomakin, N, Panchenko, E, Shogenov, Zs, Zateyshchikov, D, Klein, G, Motylev, I, Belenkiy, Di, Demin, A, Nikolaev, Ky, Oleynikov, V, Zrazhevskiy, K, Katelnitskiy, I, Khaisheva, L, Aksentiev, S, Nedoshivin, A, Popova, Vb, Agafina, As, Ballyuzek, M, Baranova, E, Burova, N, Eryshev, S, Filippov, A, Goloshchekin, Bm, Konstantinov, V, Kostenko, Va, Simanenkov, Vi, Volkova, A, Duplyakov, D, Reshetko, O, Shvarts, Y, Kuznetsov, Va, Samoylova, Yg, Tolkacheva, V, Shalaev, Sv, Khokhlov, Al, Malygin, A, Shilkina, Np, Yakusevich, Vv, Margoczy, R, Zubek, V, Dzupina, A, Dubrava, J, Dulkova, K, Fabryova, L, Gaspar, L, Kamensky, G, Kokles, M, Raslova, K, Soosova, I, Stevlik, J, Strbova, J, Sumbal, J, Uhliar, R, Micik, J, Truban, J, Fedacko, J, Pastrnakova, E, Pella, D, Fazekas, F, Ambrovicova, V, Kycina, P, Martinka, E, Nociar, J, Belicova, M, Banik, M, Kanderkova, D, Hranai, M, Duris, T, Krahulec, B, Benacka, J, Vinanska, D, Roskova, E, Skripova, D, Macek, V, Vohnout, B, Buganova, I, Engelbrecht, Jm, Pretorius, Mm, Ebrahim, Io, Bayat, J, Ganesh, S, Ranjith, N, Coetzer, Tf, Jacovides, A, Distiller, La, Hellig, Fs, Engelbrecht, Iv, Mahomed, Aa, Blignault, Sc, Burgess, Lj, Kotze, Hj, van Nieuwenhuizen, E, Musungaie, Db, Emanuel, S, van der Walt, E, Pretorius, Ce, Roos, Js, Roux, Sm, Badat, Ae, Fouche, L, Vahed, Ya, Jansen van Resburg, D, van Zyl LJ, Soto Gonzalez, A, Diaz, Jl, Segura, T, Botella 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[Boston], Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), RS: CARIM - R3.02 - Hypertension and target organ damage, MUMC+: MA Alg Interne Geneeskunde (9), Interne Geneeskunde, Ridker, P. M., Glynn, R. J., Jukema, J. W., Kastelein, J. J. P., Nicolau, J. C., Santos, R. D., Schwartz, P. F., Wright, R. S., Shear, C. L., Tardif, J. -C., SPIRE Cardiovascular Outcome Investigator, Perrone, Filardi, P, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes
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Male ,STATIN THERAPY ,Anticholesteremic Agents/adverse effects ,Antibodie ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Injections, Subcutaneous/adverse effects ,030204 cardiovascular system & hematology ,Bococizumab ,law.invention ,PCSK9 ,0302 clinical medicine ,Randomized controlled trial ,law ,Risk Factors ,GENETIC-VARIANTS ,Cardiovascular Disease ,Monoclonal ,Anticholesteremic Agent ,030212 general & internal medicine ,Myocardial infarction ,Treatment Failure ,Humanized ,Proprotein Convertase 9/antagonists & inhibitors ,Medicine(all) ,Antibodies ,Antibodies, Monoclonal, Humanized ,Anticholesteremic Agents ,Cardiovascular Diseases ,Cholesterol, LDL ,Double-Blind Method ,Female ,Follow-Up Studies ,Humans ,Hypercholesterolemia ,Injections, Subcutaneous ,Lipids ,Middle Aged ,Proprotein Convertase 9 ,Medicine (all) ,PCSK9 Inhibitors ,antibodies monoclonal humanized ,anticholesteremic agents ,cardiovascular diseases ,cholesterol, LDL ,double-blind method ,female ,follow-up studies ,humans ,hypercholesterolemia ,injections, subcutaneous ,lipids ,male ,middle aged ,proprotein convertase 9 ,risk factors ,treatment failure ,medicine (all) ,Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16] ,General Medicine ,Lipid ,3. Good health ,LDL/blood ,Multicenter Study ,Cholesterol ,TRIALS ,Cholesterol, LDL/blood ,Antibodies, Monoclonal, Humanized/adverse effects ,Randomized Controlled Trial ,subcutaneous ,lipids (amino acids, peptides, and proteins) ,Cardiovascular Diseases/prevention & control ,REDUCING LIPIDS ,Human ,medicine.medical_specialty ,animal structures ,Hypercholesterolemia/drug therapy ,Placebo ,Injections, Subcutaneou ,LDL ,Injections ,Follow-Up Studie ,EVENTS ,03 medical and health sciences ,Internal medicine ,medicine ,Journal Article ,Comparative Study ,METAANALYSIS ,Alirocumab ,business.industry ,Unstable angina ,Lipids/blood ,Risk Factor ,fungi ,Antibodies/blood ,ta3121 ,medicine.disease ,Surgery ,Evolocumab ,REDUCTION ,Humanized/adverse effects ,Subcutaneous/adverse effects ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Item does not contain fulltext BACKGROUND: Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS: In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTS: At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P/=70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of >/=100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P
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- 2017
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7. Evolocumab and clinical outcomes in patients with cardiovascular disease
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Sabatine, Marc S., Giugliano, Robert P., Keech, Anthony C., Honarpour, Narimon, Wiviott, Stephen D., Murphy, Sabina A., Kuder, Julia F., Wang, Huei, Liu, Thomas, Wasserman, Scott M., Sever, Peter S., Pedersen, Fish MP, Terje R., Abrahamsen, Te, Im, K, Kanevsky, E, Bonaca, Mp, Lira Pineda, A, Hanlon, K, Knusel, B, Somaratne, R, Kurtz, C, Scott, R, Accini Mendoza JL, Amerena, J, Badariene, J, Burgess, L, Ceska, R, Charng, Mj, Choi, D, Cobos, Jl, Dan, Ga, De Ferrari GM, Deedwania, Pc, Chopra, Vk, Erglis, A, Ezhov, Mv, Ferreira, J, Filipová, S, Gaciong, Za, Pasierski, T, Georgiev, Bg, Gonzalez-Galvez, G, Gouni-Berthold, I, Schäufele, T, Hirayama, A, Huber, K, Rammer, M, Kjaerulf Jensen, H, Wermuth, S, Jiang, L, Jukema, Jw, Kraydashenko, O, Leiter, La, Lewis, Bs, López-Miranda, J, Lorenzatti, Aj, Mach, F, Mcadam, B, Nilsson, L, Olsson, Å, Rallidis, L, Rogelio, Gg, Kerr Saraiva JF, Scheen, A, Schiele, F, Scott, Rs, Connolly, D, Siu, Cw, Tay, L, Thorgeirsson, G, Tikkanen, Mj, Tokgozoglu, Sl, 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Y, Ziegler, O, Khalife, K, Le Corvoisier, P, Motreff, P, Spaulding, C, Vanbelle, E, Bourhaial, H, Opitz, C, Kahrmann, G, Contzen, C, Appel, K, Schenkenberger, I, Rinke, A, Trenk, D, Maus, O, Karakas, M, Hanefeld, M, Darius, H, Hetzel, G, Munzel, T, Wohrle, J, Stawowy, P, Marten, I, Isermann, B, Kast, P, Vorpahl, M, Bosiljanoff, P, Hengstenberg, C, Kassner, U, Salbach, P, Fischer, M, Steiner, S, Wagner, S, Kraatz, U, von Hodenberg, E, Weyland, K, Mantas, I, Tziakas, D, Bousboulas, S, Patsilinakos, S, Mertzanos, G, Panagoulis, C, Bilianou, H, Skoumas, I, Elisaf, M, Manolis, A, Moschos, N, Kochiadakis, G, Ntaios, G, Richter, D, Athyros, V, Kolovou, G, Danias, P, Melidonis, A, Fan, K, Siu, S, Hornyik, A, Lakatos, F, Zilahi, Z, Nagy, K, Laszlo, Z, Peterfai, E, Lupkovics, G, Andreka, P, Merkely, B, Herczeg, B, Piros, G, Salamon, C, Mark, L, Papp, A, Szakal, I, Edes, I, Mohacsi, A, Tomcsanyi, J, Hajko, E, Nagy, A, Papp, E, Kiss, R, Karadi, I, Sigurdsson, A, Jain, A, Pai, R, Kothiwale, V, Kulkarni, G, Mahajan, A, Aggarwal, S, Mehta, V, Rajadhyaksha, G, Joshi, A, Khandait, V, Parmar, M, Tyagi, S, Airody Govinda, R, Dwivedi, S, Parikh, K, Pothineni, R, Solanki, B, O'Donnell, M, Crean, P, Barton, J, Shechter, M, Shotan, A, Klutstein, M, Chorin, E, Gavish, D, Kracoff, O, Atar, S, Rigler, S, Hasin, Y, Schiff, E, Merlini, P, Rapezzi, C, Pirro, M, Gonnelli, S, Floresta, A, Mennuni, M, Ardissino, D, Senni, M, Marenzi, G, Marcucci, R, Sampietro, T, Cosmi, F, Perrone Filardi, P, De Caterina, R, Fedele, F, Moretti, L, Biasucci, L, Ferri, C, Go, Y, Kiyosue, A, Higashi, Y, Tokunaga, T, Kawasaki, T, Sakagami, S, Namba, S, Saku, K, Oku, K, Arakawa, T, Iida, H, Nakamura, Y, Yamamoto, K, Hata, Y, Katsuda, Y, Koga, Y, Shimizu, M, Uehara, H, Kajiyama, S, Okamoto, H, Shinozaki, T, Fujino, Y, Funazaki, T, Higa, N, Kaigawa, K, Koike, A, Nakane, H, Sato, K, Satoh, Y, Shirasawa, K, Sugino, H, Tanabe, J, Uemura, O, Yoshimichi, G, Akai, A, Himeno, H, Inage, T, Inoko, M, Kadokami, T, Noguchi, Y, Yamashita, K, Yasumura, Y, Yuge, M, Hosokawa, S, Kawamitsu, K, Kozuma, K, Matsuo, H, Nakashima, E, Okada, M, Wada, A, Yokoya, K, Iwade, K, Kawabata, K, Tanno, H, Ako, J, Fujita, H, Izumiya, Y, Kanno, M, Nunohiro, T, Ohmura, H, Ueno, T, Kakurina, N, Jasinkevica, I, Stukena, I, Veze, I, Eglite, R, Teterovska, D, Sime, I, Strazdiene, V, Venceviciene, L, Gustiene, O, Radzeviciene-Jurgute, R, Kucinskiene, A, Maskon, O, Lee, C, Erng, T, Gan, H, Mohamed Yusof, A, Ramanathan, G, Liew, H, Lopez Alvarado, A, Nevarez Ruiz, L, De los Rios Ibarra, M, Bazzoni Ruiz, A, Ramos Lopez, G, Llamas Esperon, G, De la Pena Topete, G, Violante Ortiz, R, Illescas Diaz, J, Leon Gonzalez, S, Sanchez Diaz, C, Mendez Machado, G, Venegas Carrillo, L, Aldrete Velasco, J, Cardona Munoz, E, Leiva Pons, J, Perez Alva, J, van der Zwaan, C, Oomen, A, van de Wal, R, Magro, M, Boswijk, D, Janus, C, Groutars, R, Tonino, W, Cornel, J, Oude Ophuis, A, Troquay, R, Liem, A, Westendorp, I, Van Hessen, M, Lok, D, De Nooijer, C, Den Hartog, F, Van Beek, E, Bendermacher, P, Jansen, R, Romer, T, Rensing, B, Hersbach, F, Herrman, J, Ladyjanskaia, G, Karalis, I, Linssen, G, Bokern, M, Visman, A, Kooij, A, Monajemi, H, Lieverse, A, Baker, J, Tie, S, Risberg, K, Hysing, J, Hoivik, H, Norheim, P, Solnor, L, Hovland, A, Kjaernli, T, Jocson, G, Coching, R, Batalla, E, Go, A, Habaluyas, R, Barcinas, R, Sy, R, Estepar, R, Germar, A, Trebacz, J, Szymkowiak, K, Wnetrzak-Michalska, R, Kopaczewski, J, Przekwas-Jaruchowska, M, Kania, G, Zabowka, M, Mirek-Bryniarska, E, Dabrowska, M, Napora, P, Konieczny, M, Spyra, J, Lysek, R, Pijanowski, Z, Grzegorzewski, B, Bednarkiewicz, Z, Kinasz, L, Antkowiak-Piatyszek, K, Stania, K, Szpajer, M, Staneta, P, Skonieczny, G, Ksiezycka-Majczynska, E, Blicharski, T, Piepiorka, M, Wozakowska-Kaplon, B, Zechowicz, T, Ilkowski, J, Lubiszewska, B, Hiczkiewicz, J, Wierzbicka, K, Kosior, D, Garbocz, P, Kubica, J, Raczak, G, Wozniak, I, Cygler, J, Kramarczuk, E, Bystryk, L, Pentela-Nowicka, J, Dabrowski, M, Podolec, P, Zieba, B, Mosiewicz, J, Dubaniewicz, W, Banach, M, Tyszecka, G, Lepich, T, Rychlewska-Hanczewska, A, Guzik, T, Monteiro, P, Pereira, H, Oliveira, L, Matos, P, Soares Goncalves, S, Leitao, A, Vasco Salgado, A, Timoteo, A, Pintilei, E, Badila, E, Militaru, C, Tudoran, M, Arsenescu-Georgescu, C, Mitu, F, Zdrenghea, D, Lighezan, D, Teodorescu, I, Popescu, M, Coman, I, Vintila, M, Vishnevsky, A, Lukyanov, Y, Blokhin, A, Kostenko, V, Shvarts, Y, Markov, V, Motylev, I, Dronov, D, Sherenkov, A, Barbarash, O, Shutemova, E, Bolshakova, O, Kobalava, Z, Voevoda, M, Treshkur, T, Zrazhevskiy, K, Pimenov, L, Solovev, O, Tarasov, N, Arkhipov, M, Freidlin, M, Shalaev, S, Yakhontova, P, Shustov, S, Goloshchekin, B, Panov, A, Bart, B, Bubnova, M, Gordeev, I, Osipova, I, Tereshenko, S, Solovieva, E, Meshkov, A, Zateyshchikov, D, Tan, J, Subramaniam, T, Pella, D, Fulop, P, Antalik, L, Dzupina, A, Banikova, A, Sosovec, D, Urgeova, L, Mazur, J, Hranai, M, Banik, M, Vinanska, D, Lennerova, J, Kovar, F, Pastrnakova, E, Uhliar, R, Blasko, P, Gonsorcik, J, Lukacova, J, Oriesek, R, Hatalova, K, du Toit, M, Ebrahim, I, Vawda, G, Lipschitz, S, Blignaut, S, Engelbrecht, J, Coetzer, T, Pretorius, M, Urbach, D, Badat, A, Pillay, S, Van Zyl, L, Abelson, M, van der Walt, E, Moodley, R, Jacovides, A, Oosthuysen, W, Klug, E, Lottering, H, Kok, J, Saaiman, J, Dawood, S, De Jong, D, Kapp, C, Makotoko, E, Bayat, J, Sarvan, M, Vally, T, Stapelberg, A, Kim, M, Bae, J, Cho, Y, Kim, S, Han, K, Her, S, Kim, B, Lee, S, Hong, B, Kim, W, Rha, S, Jeong, M, Shin, G, Vida Gutierrez, M, Valdes Chavarri, M, Pinto Sala, X, Gonzalez Juanatey, J, Civeira Murillo, F, Zamorano Gomez, J, Lekuona Goya, I, Iniguez Romo, A, Cordero Fort, A, Ascaso Gimilio, J, Millan Nunez-Cortes, J, Lindholm, C, Soderberg, S, Suutari, A, Berglund, S, Mooe, T, Kusiak, D, Bandh, S, Dahlen, G, Olsson, S, Witt, N, Tyden, P, Johansson, P, Cizinsky, S, Falck, G, Pettersson, S, Rasmanis, G, Ostergren, J, Moccetti, T, Beer, H, Eberli, F, Krahenbuhl, S, Linka, A, Ackermann, D, Michel, P, Yeh, H, Tsai, C, Wu, C, Hsia, C, Juang, J, Hsieh, I, Lai, W, Huang, C, Hsieh, Y, Sahin, T, Duzenli, M, Yigit, Z, Demir, M, Yilmaz, M, Muderrisoglu, I, Kirma, C, Ercan, E, Kayikcioglu, L, Balbay, Y, Lymar, I, Kulynych, O, Prokhorov, O, Karpenko, O, Kraіz, I, Vakaliuk, I, Stanislavchuk, M, Korzh, O, Rudyk, I, Zhurba, S, Svishchenko, Y, Tseluyko, V, Gyrina, O, Reshotko, D, Kopytsya, M, Volkov, V, Myshanych, G, Rebrov, B, Rishko, M, Rudenko, L, Shatylo, V, Parkhomenko, O, Yena, L, Golovchenko, O, Sorokina, I, Malynovsky, Y, Ivan, P, Blagden, M, Dear, H, Mathew, A, Lagocki, S, Kondagunta, V, Ahsan, A, Mckinnon, C, Douglas, F, Thom, S, Fiore, G, Caulfield, M, Lynch, M, Thomas, H, Bain, S, Hall, A, Mcnally, D, Fisher, M, Keeling, P, Al-Bahrani, A, Lip, G, Ellery, A, Purohit, J, Travill, C, Cappuccio, F, Davis, G, Gaunt, R, Adlam, D, Asamoah, N, Jaafar, F, Mccormack, T, Jupp, B, Pye, M, Ainsworth, P, Chauhan, A, Paul, N, Fairlie, H, Fox, C, Muzulu, S, Trevelyan, J, Aggarwal, R, Issa, B, Saravanan, P, Cruickshank, K, Gorog, D, Heller, S, Newby, D, Nicolson, A, Hare, P, Donnelly, P, Rutherfurd, S, de Belder, M, Finlayson, J, Harvey, J, Hoye, A, Kingston, D, Sarkar, D, Negahban, A, Webster, J, Wyatt, N, Muir, S, Cummings, M, Mackenzie, I, Senior, R, Capps, N, Fotherby, K, Mcintyre, H, Aldegather, J, Dixon, L, Saksena, R, Butler, R, Ramstad, D, Pierpont, B, Levinson, D, Mohammed, A, Haddad, T, Goel, A, Dave, K, Haught, W, Desire, A, Hershon, K, Napoli, M, Tami, L, Rothschild, R, Khurana, S, Gupta, D, Cheung, D, Hearne, S, Grubb, S, Miller, A, Baird, I, Marcus, A, Srivastava, S, Forgosh, L, Fritz, R, Mays, M, Bertolet, B, Reddy, J, Khan, M, Nakhle, S, Dill, S, Fishbein, G, Khan, B, Marais, H, Reschak, M, Malone, M, Nadar, V, Whitney, R, Reichman, A, Reyes, H, El Shahawy, M, Rabinowitz, A, Weinstein, D, Farhat, N, Onyema, D, Potu, R, Runquist, L, Barnum, O, Crater, T, Fialkow, J, Shah, A, Thompson, C, Wiseman, A, Doyle, T, Henderson, D, Herzog, W, Schnitzler, R, Carr, K, Davis, M, Nagajothi, N, Olsen, S, Rogers, W, Rubino, J, Singh, I, Tarleton, G, Bhagwat, R, Clardy, D, Jardula, M, Robinson, J, Torres, M, Vijay, N, Farris, N, Lillo, J, Moriarty, P, Recknor, C, Berlacher, P, Christensen, T, Gabra, N, Issa, M, Janik, M, Lawless, A, Molter, D, Stout, E, Brezina, B, Claxton, E, Linsky, R, Poock, J, Remler, R, Roseman, H, Schramm, E, Al-Joundi, T, Amin, J, Hitchcock, J, Isserman, S, Kirstein, J, Rider, J, Shalek, M, Sherman, H, Bernstein, M, Chandra, L, Hatharasinghe, R, Ibrahim, H, Iteld, B, Linzmeyer, K, Seaton, B, Zeig, S, Christofides, E, Dunbar, R, Griffin, S, Kohli, N, Koren, M, Pharr, W, Purdy, D, Spencer, R, Yeoman, G, Banerjee, S, Cheek, H, Engel, E, Hamroff, G, Huling, R, Kozlowski, L, Levin, P, Makam, S, Meengs, M, Bhushan, R, Erickson, B, Herman, L, Lo, E, Mcdowell, E, Mcgrew, F, Miller, M, Ord, J, Webel, R, Wilhoit, G, Wise, J, Yang, E, Budoff, M, Collins, J, Dauber, I, Dobkin, L, Focil, A, Gandy, W, Pasquini, J, Ramos, M, Rodriguez, D, Rosenson, R, Sanford, K, Schlau, A, Snyder, B, Stonesifer, L, Tang, A, De Souza, J, Elam, M, French, J, Guyton, J, Hage Korban, E, Kereiakes, D, King, M, Loh, I, Navarro, J, Simons, R, Tobin, T, Younis, L, Aboufakher, R, Baldari, D, Ballantyne, C, Broughton, R, Eaton, C, Johnston, J, Simon, W, Thomson, S, Vora, K, Youngman, D, Alzohaili, O, Auerbach, E, Brown, C, Burrough, B, Chen, Y, Gilpatrick, M, Landzberg, J, Mitchell, C, Rice, L, Rubenfire, M, Sofley, C, Strobl, D, Atassi, K, Davila, W, Diogo, J, Fagan, T, Joffe, I, Krishna, J, Osea, E, Penny, W, Rowe, W, Shapiro, M, Welker, J, Benton, R, Dobratz, D, Fortuin, F, Graham, J, Henry, B, Kusnick, B, Lutskiy, M, Mcrae, A, Saway, W, Scott, J, Shah, M, Weinberg, B, Zarich, S, Acheatel, R, Case, C, Earl, J, Fernandez, S, Giugliano, G, Handelsman, Y, Hermany, P, Holder, S, Kashyap, M, Khan, A, Lader, E, Peniston, J, Raoof, T, Sacco, J, Shore, K, Spriggs, D, Stringam, S, Tahirkheli, N, Delgado, E, Derian, W, Greenwald, J, Harris, M, Jackson, R, Marhefka, G, Mcelveen, W, Mooss, A, Morris, P, Murray, J, Pearlstein, P, Raisinghani, A, Rezkalla, S, Sakhrani, L, Schreibman, D, Shaoulian, E, Steinsapir, J, Yataco, A, De La Cruz, A, Fredrick, M, Goldenberg, E, Lee, D, Mccullum, K, Mclellan, B, Stephens, L, Wilson, S, Alfieri, A, Mandviwala, M, Orourke, D, Samal, A, Schmedtje, J, Waxman, F, Carhart, R, Clements, B, Dyke, C, Ghali, J, Gruberg, L, Hack, T, Jehle, A, Pogue, B, Schooley, C, and Shifrin, G
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Male ,STATIN THERAPY ,2700 General Medicine ,Disease ,Cardiovascular ,PLACEBO-CONTROLLED TRIAL ,Gastroenterology ,0302 clinical medicine ,Anticholesteremic Agent ,Medicine ,Myocardial infarction ,11 Medical and Health Sciences ,ddc:616 ,Incidence ,Antibodies, Monoclonal ,General Medicine ,Cholesterol ,Cardiovascular Diseases ,Monoclonal ,Drug Therapy, Combination ,Proprotein Convertase 9 ,Antibody ,Aged ,Anticholesteremic Agents ,Atherosclerosis ,Cholesterol, LDL ,Double-Blind Method ,Female ,Follow-Up Studies ,Humans ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Hypercholesterolemia ,Least-Squares Analysis ,Middle Aged ,Medicine (all) ,REDUCING LIPIDS ,Human ,medicine.medical_specialty ,Evinacumab ,Clinical Trials and Supportive Activities ,PCSK9 INHIBITION ,Follow-Up Studie ,LDL ,03 medical and health sciences ,Drug Therapy ,Clinical Research ,LDL-C ,Least-Squares Analysi ,Science & Technology ,Unstable angina ,PCSK9 ,medicine.disease ,chemistry ,Clinical Biochemistry ,030204 cardiovascular system & hematology ,Bococizumab ,FOURIER Steering Committee and Investigators ,Medical and Health Sciences ,chemistry.chemical_compound ,Antibodies monoclonal ,Cardiovascular Disease ,030212 general & internal medicine ,Stroke ,Humanized ,RISK ,biology ,PCSK9 Inhibitors ,10051 Rheumatology Clinic and Institute of Physical Medicine ,Heart Disease ,Atherosclerosi ,6.1 Pharmaceuticals ,Combination ,Cardiology ,Life Sciences & Biomedicine ,Antibodies, Monoclonal, Humanized ,EZETIMIBE ,610 Medicine & health ,Antibodies ,Medicine, General & Internal ,General & Internal Medicine ,Internal medicine ,CORONARY-HEART-DISEASE ,In patient ,Heart Disease - Coronary Heart Disease ,Alirocumab ,Ldl cholesterol ,business.industry ,Evaluation of treatments and therapeutic interventions ,Evolocumab ,Good Health and Well Being ,Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE ,biology.protein ,MODERATE ,Hydroxymethylglutaryl-CoA Reductase Inhibitor ,business - Abstract
Background Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. Methods We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. Results At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P
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- 2017
8. Mutation analysis in a small cohort of New Zealand patients originating from the United Kingdom demonstrates genetic heterogeneity in familial hypercholesterolemia
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Thiart, R, Varret, M, Lintott, CJ, Scott, RS, Loubser, O, du Plessis, L, de Villiers, JNP, Boileau, C, and Kotze, MJ
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- 2000
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9. Baseline circulating FGF21 concentrations and increase after fenofibrate treatment predict more rapid glycemic progression in type 2 diabetes: Results from the FIELD study
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Ong, KL, O'Connell, R, Januszewski, AS, Jenkins, AJ, Xu, A, Sullivan, DR, Barter, PJ, Scott, RS, Taskinen, MR, Waldman, B, Colman, PG, Best, JD, Simes, JR, Rye, KA, Keech, AC, Ong, KL, O'Connell, R, Januszewski, AS, Jenkins, AJ, Xu, A, Sullivan, DR, Barter, PJ, Scott, RS, Taskinen, MR, Waldman, B, Colman, PG, Best, JD, Simes, JR, Rye, KA, and Keech, AC
- Abstract
BACKGROUND: It is not known whether circulating fibroblast growth factor 21 (FGF21) concentrations are associated with glycemic progression in patients with established type 2 diabetes. This study reports this relationship in type 2 diabetes patients participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. METHODS: Plasma FGF21 was quantified in 9697 study participants. Among patients with lifestyle-only glucose control measures at baseline, glycemic progression was defined as the initiation of oral hypoglycemic agents or insulin therapy. We assessed the relationship of FGF21 concentrations with glycohemoglobin (Hb A1c), the homeostasis model assessment of ß-cell function (HOMA-B) and insulin resistance (HOMA-IR), and glycemic progression. RESULTS: Among 2584 patients with lifestyle-only glycemic therapy at baseline, plasma FGF21 concentrations were positively associated with HOMA-IR (5.1% increase per 100% increase in FGF21 concentrations). Patients with higher baseline plasma FGF21 concentrations had higher risk of glycemic progression over a 5-year period (P=0.02), but the association was not significant after further adjusting for alanine aminotransferase (ALT) enzyme activity. During the fenofibrate active run-in phase, higher tertiles of fenofibrate-induced increase in FGF21 concentrations were associated with higher risk of glycemic progression (adjusted hazards ratio =1.09 and 1.18 for tertiles 2 and 3, respectively, P for trend = 0.01), even after adjusting for ALT enzyme activity. This association was statistically significant in the fenofibrate group only (P = 0.01). CONCLUSIONS: Higher baseline and fenofibrate-induced increase in FGF21 concentrations predict more rapid glycemic progression in type 2 diabetes patients. This association may be partly explained by hepatic function.
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- 2017
10. Epstein-Barr virus in the pathogenesis of oral cancers
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Guidry, JT, primary, Birdwell, CE, additional, and Scott, RS, additional
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- 2017
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11. Relationship of fibroblast growth factor 21 with baseline and new on-study microvascular disease in the Fenofibrate Intervention and Event Lowering in Diabetes study
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Ong, KL, Januszewski, AS, O’Connell, R, Buizen, L, Jenkins, AJ, Xu, A, Sullivan, DR, Barter, PJ, Scott, RS, Taskinen, MR, Rye, KA, Keech, AC, Ong, KL, Januszewski, AS, O’Connell, R, Buizen, L, Jenkins, AJ, Xu, A, Sullivan, DR, Barter, PJ, Scott, RS, Taskinen, MR, Rye, KA, and Keech, AC
- Abstract
Aims/hypothesis: Baseline circulating fibroblast growth factor 21 (FGF21) levels can predict total cardiovascular disease events in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. This paper describes the relationship of baseline FGF21 levels and new on-study microvascular disease in patients with type 2 diabetes from the FIELD study. Methods: Baseline FGF21 levels were measured in plasma by enzyme-linked immunosorbent assay in 9697 study participants. Total microvascular disease was defined as the presence of any nephropathy, retinopathy, neuropathy and/or microvascular amputation. The relationship between FGF21 levels and microvascular disease was assessed by multivariable logistic regression. Results: Higher baseline FGF21 levels were found in patients with baseline total microvascular disease (p < 0.001). The association remained significant after adjusting for potential confounding factors (OR [95% CI] 1.13 [1.08, 1.19] per SD increase in loge-transformed FGF21 levels, p < 0.001). Of 6465 patients without baseline total microvascular disease, 1517 developed new on-study total microvascular disease over 5 years of follow-up. Higher baseline FGF21 levels were associated with a higher risk of new on-study total microvascular disease after adjusting for potential confounding factors (OR [95% CI] 1.09 [1.02, 1.16] per SD increase in loge-transformed FGF21 levels, p = 0.01). Addition of FGF21 levels in a model of new on-study total microvascular disease with established risk factors significantly, but modestly, increased the integrated discrimination improvement and the net reclassification improvement (both p < 0.01). Conclusions/interpretation: Higher baseline FGF21 levels are seen in patients with type 2 diabetes and established microvascular disease, and predict the future development of new microvascular disease.
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- 2015
12. The relationship of fibroblast growth factor 21 with cardiovascular outcome events in the Fenofibrate Intervention and Event Lowering in Diabetes study
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Ong, KL, Januszewski, AS, O’Connell, R, Jenkins, AJ, Xu, A, Sullivan, DR, Barter, PJ, Hung, WT, Scott, RS, Taskinen, MR, Keech, AC, Rye, KA, Ong, KL, Januszewski, AS, O’Connell, R, Jenkins, AJ, Xu, A, Sullivan, DR, Barter, PJ, Hung, WT, Scott, RS, Taskinen, MR, Keech, AC, and Rye, KA
- Abstract
© 2014, Springer-Verlag Berlin Heidelberg. Aims/hypothesis: Circulating fibroblast growth factor 21 (FGF21) levels are often elevated in obesity, dyslipidaemia, insulin resistance and type 2 diabetes. This study investigated the relationship of plasma FGF21 levels with cardiovascular events in patients with type 2 diabetes.Methods: Plasma FGF21 levels were measured by ELISA at baseline in 9,697 individuals with type 2 diabetes participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. We assessed the association of FGF21 levels with the incidence of different cardiovascular outcomes over 5 years. The primary outcome was total cardiovascular disease (CVD) events and the secondary outcomes were the four individual components: coronary heart disease events, total stroke, CVD mortality and coronary and carotid revascularisation. The tertiary outcome was hospitalisation for angina pectoris.Results: Higher baseline FGF21 levels were associated with higher risks of all cardiovascular outcome events after adjusting for the study treatment allocation (all p < 0.01). The associations remained significant for total CVD events and for coronary and carotid revascularisation after further adjusting for confounding factors, with the HR (95% CI) being 1.28 (1.10, 1.50) and 1.26 (1.01, 1.56), respectively, for the highest tertile compared with the lowest tertile (overall effect p = 0.002 and 0.007, respectively). The addition of FGF21 levels to a model including established CVD risk factors predicting total CVD events led to a non-significant increase in the C-statistic but there was a significant improvement in integrated discrimination and net reclassification.Conclusions/interpretation: Higher baseline plasma FGF21 levels were associated with higher risk of cardiovascular events in patients with type 2 diabetes.
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- 2015
13. Formation, Mugla, SW Turkey
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Kaya, TT, Mayda, S, Kostopoulos, DS, Alcicek, MC, Merceron, G, Tan, A, Karakutuk, S, Giesler, AK, and Scott, RS
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Mammals ,Neogene ,Turolian ,Biochronology ,Turkey - Abstract
Here we report on a new fossil locality, Serefkoy-2, from the Yatagan Basin of southwestern Turkey that preserves a well-sampled, abundant, and diverse mammal fauna. Indeed, after three field seasons, more than 1200 catalogued specimens representing 26 mammal species belonging to 14 genera make the Serefkoy-2 mammalian assemblage one of the richest Late Miocene fauna from Anatolia. Five hipparionines, six bovids, including the rare and enigmatic Urmiatherium rugosifrons and the presence of Pliohyrax graecus, strongly support affinities with Late Miocene faunas from Samos Island, Greece. Through a consideration of the identified material and the subsequent comparison with material from well-known Balkan and Anatolian faunas, a Middle Turolian (MN12) age for Serefkoy-2 is indicated. (C) 2011 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
- Published
- 2012
14. Pharmacokinetic comparison of a generic coenzyme q(10) solubilizate and a formulation with soybean phytosterols.
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Young JM, Molyneux SL, Florkowski CM, Frampton CM, George PM, and Scott RS
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Coenzyme Q(10) (CoQ(10) ) is essential for all cells, and deficiency has been implicated in cardiovascular disease. Plant phytosterols inhibit cholesterol absorption, and may thereby also reduce cardiovascular risk. This study compared the relative bioavailability of CoQ(10) solubilized in low-dose soybean phytosterols (SterolQ(10) ) with a generic CoQ(10) solubilizate. In a randomized, cross-over design, 36 healthy males received a single 100 mg dose of CoQ(10) , as SterolQ(10) or generic CoQ(10) , with a two-week washout between treatments. Plasma CoQ(10) was analysed at baseline, and at 2, 4, 6, 8 and 10 h after supplement ingestion. Subjects were then administered either 100 mg/day of generic CoQ(10) or SterolQ(10) for 4 weeks. Fasting plasma CoQ(10) levels were measured at baseline and following supplementation. The two preparations were bioequivalent in regard to the area under the curve (AUC(0-10h) ) and maximum increase in concentration (C(max) ), with geometric mean ratios of 0.89 (CI 0.81-0.98) and 0.88 (CI 0.80-0.96), respectively. Four-weeks of CoQ(10) resulted in a comparable twofold increase in CoQ(10) levels for both formulations (p < 0.001), which was similar between preparations (p = 0.74). The combined CoQ(10) and phytosterol formulation, SterolQ(10) , showed bioequivalence to the generic CoQ(10) following a single CoQ(10) dose, and demonstrated comparable bioavailability following multiple dose administration. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
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- 2012
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15. Relative glycaemic impact of customarily consumed portions of eighty-three foods measured by digesting in vitro and adjusting for food mass and apparent glucose disposal.
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Monro JA, Wallace A, Mishra S, Eady S, Willis JA, Scott RS, and Hedderley D
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Practical values to guide food choices for control of postprandial glycaemia need to refer to entire foods in amounts customarily consumed. We tested an in vitro method for determining the relative glycaemic impact (RGI) of customarily consumed portions of foods. Sugars released during in vitro pancreatic digestion of eighty-three foods were measured as glucose equivalents (GE) per gram of food, adjusted by the glycaemic indexes of the sugars to obtain glycaemic GE (GGE) per gram and multiplied by food portion weight to obtain the GGE contribution of the food portion, its RGI. The results were compared with clinical GGE values from subjects who consumed the same food amounts. In vitro and in vivo GGE values were significantly correlated, but the slope of the regression equation was significantly less than one, meaning in vitro GGE values overestimated in vivo GGE values. Bland-Altman method comparison showed the in vitro-in vivo disparity to increase as mean GGE increased, suggesting the need to allow for different rates of homeostatic blood glucose disposal (GD) due to different GGE doses in the customarily consumed food portions. After GD correction, Bland-Altman method comparison showed that the bias in predicting in vivo GGE values from in vitro GGE values was almost completely removed (y = 0.071x - 0.89; R2 0.01). We conclude that in vitro food values for use in managing the glycaemic impact of customarily consumed food quantities require correction for blood GD that is dependent on the GGE content of the food portions involved. [ABSTRACT FROM AUTHOR]
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- 2010
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16. THE SPECIFICITY OF NEMATODE ALLERGENS IN THE DIAGNOSIS OF HUMAN VISCERAL LARVA MIGRANS.
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Hogarth-Scott, RS and Feery, Brian J
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- 1976
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17. A peer evaluation for measuring team teaching effectiveness.
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Rabada-Rice F and Scott RS
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- 1986
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18. The effectiveness of diabetes education for non-insulin-dependent diabetic persons.
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Scott RS, Stafford JM, and Beaven DW
- Published
- 1984
19. Clinical and Pathological Report of Bilateral Glioma Retinæ
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Moore Rf and Scott Rs
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Pathology ,medicine.medical_specialty ,Text mining ,business.industry ,Glioma ,Medicine ,Library science ,business ,medicine.disease ,Pathological - Published
- 1929
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20. Alzheimer's: questions children ask.
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Scott RS
- Published
- 1989
21. The current status of IgE in allergic reactions
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Hosking Cs, Simons Mj, and Hogarth-Scott Rs
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Erythrocytes ,biology ,business.industry ,Radioimmunoassay ,General Medicine ,Haplorhini ,History, 20th Century ,Immunoglobulin E ,Antigen-Antibody Reactions ,Iodine Radioisotopes ,Immunoglobulin M ,Immunoglobulin G ,Immunology ,biology.protein ,Hypersensitivity ,Medicine ,Animals ,Humans ,gamma-Globulins ,Current (fluid) ,business - Published
- 1970
22. THE SPECIFICITY OF NEMATODE ALLERGENS IN THE DIAGNOSIS OF HUMAN VISCERAL LARVA MIGRANS
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Hogarth-Scott, RS, primary and Feery, Brian J, additional
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- 1976
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23. Dilemmas in practice: when it isn't life or death... when the aging parents can no longer live independently.
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Scott RS
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- 1985
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24. Evaluation of lactate methods on the radiometer ABL 725, i-STAT CG4+ cartridge, Nova Biomedical Lactate Plus, Roche Integra 400 Plus, and Vitros 750 analyzers.
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Scott RS, Vlassoff D, Karon BS, and Santrach PJ
- Published
- 2007
25. The Papanicolaou test and screening for cervical cancer.
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Vasilev SA, Scott RS, Vasilev, S A, and Scott, R S
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- 1997
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26. Effect of coenzyme q(10) supplementation on simvastatin-induced myalgia.
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Young JM, Florkowski CM, Molyneux SL, McEwan RG, Frampton CM, George PM, and Scott RS
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- 2007
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27. Pleural Plaques from Secondhand Asbestos Exposure.
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Chillag S and Morehead RS
- Published
- 2024
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28. Physical Activity Monitoring in Children in the 1-Year After 3 or More Days of Invasive Ventilation: Feasibility of Using Accelerometers.
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Maddux AB, Miller KR, Sierra YL, Bennett TD, Watson RS, Spear M, Pyle LL, and Mourani PM
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Objectives: To measure physical activity in a cohort of children who survived greater than or equal to 3 days of invasive ventilation., Design: Prospective cohort study (2018-2021)., Setting: Quaternary children's hospital PICU., Patients: Children (2-17 yr old) without a preexisting tracheostomy who were ambulatory pre-illness and received greater than or equal to 3 days of invasive ventilation., Interventions: None., Measurements and Main Results: We measured duration and intensity of physical activity using hip- (< 6 yr old) or wrist- (≥ 6 yr old) worn ActiGraph GT3XP-BTLE accelerometers (ActiGraph, Pensacola, FL) for 7 days at three timepoints: hospital discharge, 3 months, and 12 months post-discharge. We measured duration of moderate or vigorous physical activity (MVPA) and nonsedentary activity, both characterized as percent of total awake wear time and total minutes per day. We categorized participants based on when they first attained a "high activity" day defined as greater than or equal to 60 minutes of MVPA or a day with percent of MVPA in the top quartile of all days measured. We evaluated 55 children of whom 43 (78%) had data from greater than or equal to 1 timepoint including 19 (35%) with data from all timepoints. Maximum daily MVPA increased across the three post-discharge timepoints (median, 16.0 min [interquartile range (IQR), 8.0-42.8 min], 48.3 min [27.8-94.3 min], and 68.4 min [34.7-111.0 min], respectively) as did maximum daily percent of awake wear time in MVPA (median, 4.3% [IQR, 2.8-9.0%], 10.1% [5.7-14.4%], and 11.1% [7.1-17.5%], respectively). Of the 43 participants, 27 achieved a high activity day: nine of 43 during the hospital discharge period, 14 of 43 during the 3 months post-discharge period, and four of 43 during the 12 months post-discharge period; 16 of 43 did not demonstrate high activity during the post-discharge year., Conclusions: In the 1-year after PICU discharge measuring physical activity with accelerometers in children 2-17 years old is feasible. Furthermore, demonstration of variable recovery trajectories in our pilot cohort suggests it has potential to be an outcome measure in clinical trials., Competing Interests: Dr. Maddux’s institution received funding from the National Institute of Child Health and Human Development (NICHD; K23HD096018) and the Francis Family Foundation. Drs. Maddux, Miller, Sierra, Bennett, and Mourani received support for article research from the National Institutes of Health. Dr. Bennett’s institution received funding from the National Heart, Lung, and Blood Institute, the NICHD, and the National Center for Advancing Translational Sciences. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)
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- 2024
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29. Decisional Control Preferences in Managing Intraductal Papillary Mucinous Neoplasms of the Pancreas.
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England B, Habib JR, Sharma AR, Hewitt DB, Bridges JFP, Javed AA, Wolfgang CL, Braithwaite RS, and Sacks GD
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Objectives: To evaluate patient preferences for decision-making role in the management of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas and to identify individual characteristics associated with those preferences., Background: Management of IPMNs is rooted in uncertainty with current guidelines failing to incorporate patients' preferences and values., Methods: A representative sample of participants aged 40-70 were recruited to evaluate a clinical vignette where they were given the option to undergo surveillance or surgical resection of their IPMN. Their preferred role in the decision-making process for the vignette was evaluated using the Control Preference Scale. The relationship between control preference and variables including cancer anxiety, health literacy, and education level was analyzed., Results: Of the 520 participants in the study, most preferred an active role (65%), followed by shared (29%), and passive roles (6%) in the decision-making process. Lower health literacy was significantly associated with a more passive control preference (p = 0.003). Non-active preference was significantly associated with Latino race compared to White race (odds ratio = 0.52, p = 0.009) in multivariate analysis. We found no significant association between control preference and education level or cancer anxiety., Conclusions: Most patients preferred an active role in IPMN treatment decisions. Lower health literacy and Latino race were associated with a preference for non-active decision roles. Clinicians should strive to align patient involvement in IPMN treatment decisions with their patient's preferred role., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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30. A Vaccine Clinic for Individuals With Neurodevelopmental Disabilities.
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Ma VK, Roseborough E, Tuss V, Mello M, Owens KH, Stahmer A, and Akins RS
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- 2024
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31. Prediction Model for Outpatient Opioid Use Following the Minimally Invasive Repair of Pectus Excavatum.
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Eldredge RS, Ochoa B, Orcutt E, Hunteman Z, Rassam K, Lee J, and Padilla BE
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- Humans, Male, Retrospective Studies, Adolescent, Female, Ambulatory Care statistics & numerical data, Pain Management methods, Funnel Chest surgery, Analgesics, Opioid therapeutic use, Analgesics, Opioid administration & dosage, Pain, Postoperative drug therapy, Minimally Invasive Surgical Procedures methods
- Abstract
Introduction: To minimize unused outpatient opioids while providing adequate pain control, we sought to create a model to predict outpatient opioid use following the minimally invasive repair of pectus excavatum with cryoablation MIRPE-C., Methods: A retrospective review was conducted at a single center from May 2023 to January 2024 among patients <21 years who underwent MIPRE-C. Demographic and clinical data, including inpatient and outpatient opioid use were reviewed. Patients completed opioid use questionnaires at their first postoperative visit. Simple linear regression was employed to create a model for outpatient opioid use., Results: Sixty-eight patients underwent MIRPE-C: 84% were male (mean age of 15.2 ± 1.7 years, and median Haller index 4.2[IQR:3.7-5.7]). Daily mean inpatient opioid requirement and daily opioid doses were 0.3 ± 0.2 OME/day/kg and 2 ± 1.2 opioid doses/day. At the first outpatient follow-up visit, patients reported using a median of five 5-mg oxycodone tablets [IQR:1.6-10] for 5 days [IQR:2-7] with 22% of patients needing an opioid refill. On linear regression, inpatient opioid use had a significant relationship with the number of outpatient doses taken, while patient factors were not associated with outpatient opioid use. A simple equation for predicting opioid need based on best fit (R
2 = 0.211) was developed: #OUTPATIENT OPIOID TABLETS = 3 TABLETS + (0.82 x #INPATIENT OPIOID RECIEVED)., Conclusion: The proposed outpatient opioid prescription model is simple to calculate and tailors the prescription to individual patient need. This model has the potential to provide effective pain control and avoid prescription refills, while minimizing over-prescription of opioids., Level of Evidence: Treatment study Level III., Competing Interests: Conflict of interest Dr. Padilla is an education consultant for Atricure. The other authors have no relevant financial or non-financial interests to disclose. No funding was received for conducting this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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32. Cervical spine clearance in the pediatric trauma population: What you need to know.
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Russell KW, Kahan A, and Eldredge RS
- Abstract
Abstract: Evaluation of the pediatric cervical spine after blunt trauma is an important topic that requires special consideration. In this article, we will review background information and differences between the pediatric and adult cervical spine. We will then give up-to-date guidance on best practice for screening and clearance of the cervical spine in children, including the advantages and disadvantages of different imaging techniques. Finally, we will introduce current topics of study and surmise what changes or innovations may be coming in the future., Level of Evidence: Expert Review, Level VI., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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33. Serosurvey of Arboviruses in Free-ranging Mantled Howler Monkeys (Alouatta palliata) in Costa Rica.
- Author
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Larsen RS, Moresco A, Karabatsos N, Dolz G, and Glander KE
- Abstract
We investigated the prevalence of arthropod-borne viral diseases in a population of free-ranging mantled howler monkeys (Alouatta palliata) in Costa Rica in 1998. Blood samples were opportunistically collected from monkeys anesthetized for another study. Serology was performed on 64 individuals to assess exposure of this population to vesicular stomatitis virus, equine encephalitis viruses, Mayaro virus, St. Louis encephalitis virus, yellow fever virus, and dengue virus. The New Jersey serotype of vesicular stomatitis (VSV-NJ) was the only pathogen for which the population tested positive (44% [28/64]). This is the first report of antibodies against VSV-NJ in nonhuman primates in Costa Rica., (© Wildlife Disease Association 2024.)
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- 2024
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34. Distinct Molecular Profiles Underpin Mild-To-Moderate Equine Asthma Cytological Profiles.
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Karagianni AE, Richard EA, Toquet MP, Hue ES, Courouce-Malblanc A, McGorum B, Kurian D, Aguilar J, Mazeri S, Wishart TM, and Pirie RS
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- Horses, Animals, Neutrophils metabolism, Neutrophils immunology, Mast Cells metabolism, Mast Cells pathology, Transcriptome genetics, Proteomics methods, Inflammation pathology, Eosinophils metabolism, Eosinophils pathology, Gene Expression Profiling, Asthma pathology, Asthma genetics, Asthma immunology, Bronchoalveolar Lavage Fluid cytology, Horse Diseases pathology, Horse Diseases immunology, Horse Diseases metabolism
- Abstract
A state-of-the-art multi-omics approach was applied to improve our understanding of the aetio-pathogenesis of a highly prevalent, performance-limiting disorder of racehorses: mild-to-moderate equine asthma (MMEA). This is a prerequisite to improving prophylactic, management, and therapeutic options for this condition. Although a number of risk factors have been identified, options for intervention are limited. This study applied a multi-omic approach to reveal key inflammatory pathways involved in inflammatory cell recruitment to the lower airways and highlight distinct MMEA inflammatory profiles. We compared bronchoalveolar lavage fluid (BALF) cell gene and protein expression data from horses with non-inflammatory BALF cytology with those isolated from horses with neutrophilic, mastocytic, mixed neutrophilic/mastocytic, and eosinophilic/mastocytic inflammation. The analyses on transcriptomic/proteomic data derived from BALF from horses with neutrophilic cytology showed enrichment in classical inflammatory pathways, and horses with mastocytic inflammation showed enrichment in pathways involved in hypersensitivity reactions related to nonclassical inflammation potentially mimicking a Th2-immune response. The mixed eosinophilic/mastocytic group also presented with a nonclassical inflammatory profile, whereas the mixed neutrophilic/mastocytic group revealed profiles consistent with both neutrophilic inflammation and hypersensitivity. Our adopted multi-omics approach provided a holistic assessment of the immunological status of the lower airways associated with the different cytological profiles of equine asthma.
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- 2024
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35. Chromatographic Determination of Permeability-Relevant Lipophilicity Facilitates Rapid Analysis of Macrocyclic Peptide Scaffolds.
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Koch G, Engstrom A, Taechalertpaisarn J, Faris J, Ono S, Naylor MR, and Lokey RS
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- Dogs, Madin Darby Canine Kidney Cells, Animals, Hydrophobic and Hydrophilic Interactions, Permeability, Cell Membrane Permeability, Macrocyclic Compounds chemistry, Macrocyclic Compounds pharmacology, Peptides, Cyclic chemistry, Peptides, Cyclic pharmacology, Peptides, Cyclic metabolism
- Abstract
Hydrocarbon-determined shake-flask measurements have demonstrated great utility for optimizing lipophilicity during early drug discovery. Alternatively, chromatographic methods confer reduced experimental error and improved handling of complex mixtures. In this study, we developed a chromatographic approach for estimating hydrocarbon-water shake-flask partition coefficients for a variety of macrocyclic peptides and other bRo5 molecules including PROTACs. The model accurately predicts experimental shake-flask measurements with high reproducibility across a wide range of lipophilicities. The chromatographic retention times revealed subtle conformational effects and correlated with the ability to sequester hydrogen bond donors in low dielectric media. Estimations of shake-flask lipophilicity from our model also accurately predicted trends in MDCK passive cell permeability for a variety of thioether-cyclized decapeptides. This method provides a convenient, high-throughput approach for measuring lipophilic permeability efficiency and predicting passive cell permeability in bRo5 compounds that is suitable for multiplexing pure compounds or investigating the properties of complex library mixtures.
- Published
- 2024
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36. Cortico-limbic volume abnormalities in late life depression are distinct from β amyloid and white matter pathologies.
- Author
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Mackin RS, Rhodes E, Kassel M, Kryza-Lacombe M, Burns E, Bickford D, Morin R, Tosun D, Landau S, Butters MA, Aisen P, Raman R, Saykin AJ, Toga A, Koeppe R, Jack C, Weiner MW, Nelson C, and Insel PS
- Abstract
This study was conducted to clarify patterns of cortico-limbic volume abnormalities in late life depression (LLD) relative to non-depressed (ND) adults matched for amyloid β (Aβ) deposition and to evaluate the relationship of volume abnormalities with cognitive performance. Participants included 116 LLD and 226 ND. Classification accuracy of LLD status was estimated using area under the receiver operator characteristic curve. Twenty-one percent of LLD and ND participants were Aβ positive and the groups did not differ on white matter hyperintensity volume (WMH (logscale); β = 0.12, p = 0.28). Compared to ND, the LLD group exhibited significantly lower bilateral volume in the lateral orbitofrontal cortex, hippocampus, accumbens area, superior temporal lobe, temporal pole, and amygdala after multiple comparison correction (p < 0.009 for all). Cortico-limbic volumes significantly improved classification of LLD beyond demographic characteristics, Aβ status, and WMH (AUC
Vol = 0.71, AUCWMH ,Aβ = 0.62, AUC difference, 0.09 [0.03 to 0.15]). LLD exhibited poorer performance on measures of global cognition, set shifting, and verbal learning and memory relative to ND. Cognitive function was positively associated with cortico-limbic volumes and these relationships did not differ by group. Secondary analyses with an ND sample additionally matched for Mild Cognitive Impairment (MCI) diagnosis showed a similar but attenuated pattern of volume abnormalities. Overall, our results support LLD as being associated with cortico-limbic volume abnormalities that are distinct from Aβ and white matter pathologies and that these volume abnormalities are important factors associated with cognitive dysfunction in LLD., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2024
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37. Lipoprotein (a): Underrecognized Risk with a Promising Future.
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Manzato M, Wright RS, Jaffe AS, and Vasile VC
- Abstract
Lipoprotein a (Lp(a)) is a lipid biomarker that binds cholesterol and bears independent cardiovascular risk. Strategies to lower the level of Lp(a) and mitigate such risk are important both for primary and secondary prevention. Currently there are no approved therapies targeting Lp(a) directly. Lipid lowering therapies prescribed routinely may have no effect on Lp(a) levels. Some agents such as niacin and estrogens can significantly decrease Lp(a), but their use is not recommended due to their adverse safety profile. Statins increase Lp(a) levels by 10-20%, questioning the benefit of such therapy when this biomarker is elevated. The Food and Drug Administration (FDA) endorses new agents to address dyslipidemia such as proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i) and Inclisiran, a small interfering RNA. These approaches have been shown to also significantly reduce Lp(a), but more clinical data is needed before implementing their use in clinical practice. Clinical trials are currently ongoing to test the efficacy of newly developed antisense oligonucleotides and small interfering RNAs targeting the gene encoding for Lp(a) in hepatocytes, while other investigations assess small molecules that inhibit Lp(a) assembly. This review summarizes the pathophysiology and clinical implications of Lp(a) elevation, and focuses on proposed Lp(a) therapies and the current state of the clinical trials of such novel agents., Competing Interests: Matteo Manzato has no conflict of interest; Dr. Vasile has no conflict of interest; Dr. Jaffe presently or in the past has consulted for most of the major in vitro diagnostic companies. He also consults for Moderna and has stock options in RCE Technologies; Dr. Wright reports receiving advisory board fees from Boehringer Ingelheim and past fees for consulting on lipid issues with The Medicines Company., (Copyright: © 2024 The Author(s). Published by IMR Press.)
- Published
- 2024
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38. Postoperative Wound Infection After Primary Closure in Pediatric Dog Bite Injuries.
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Ochoa B, Eldredge RS, Gilbert M, Padilla B, Notrica DM, Armstrong C, Ballan W, and Lee J
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- Animals, Dogs, Humans, Child, Retrospective Studies, Male, Female, Child, Preschool, Adolescent, Incidence, Wound Closure Techniques, Infant, Bites and Stings surgery, Bites and Stings epidemiology, Bites and Stings complications, Surgical Wound Infection prevention & control, Surgical Wound Infection etiology, Surgical Wound Infection epidemiology, Antibiotic Prophylaxis methods, Anti-Bacterial Agents therapeutic use
- Abstract
Introduction: Guidelines recommend three to 5 d of antibiotic prophylaxis after dog bite injury, but variation exists in clinical practice after primary closure of wounds. The purpose of this study was to analyze antibiotic duration and incidence of infection during a study period in which an institutional protocol limiting postrepair antibiotics to a maximum of 3 d was implemented., Methods: Dog bite injuries that underwent primary closure in patients ≤18 y were retrospectively identified from 2018 to 2022 at a level 1 pediatric trauma center. Demographic and clinical data were collected. Protocol compliance and short course of antibiotics were defined as ≤3 d of antibiotics. Multivariable regression analysis for variables associated with wound infection was performed., Results: 455 injuries were included for analysis. After protocol implementation, the mean antibiotic duration decreased from 6.8 to 4.4 d (P < 0.001). Postrepair follow-up data were available for 235 (51.6%) cases in the cohort. Multivariable logistic regression identified superficial wounds and anatomic injury location to be significantly associated with wound infection. Shorter antibiotic duration was not associated with increased risk of wound infection on regression analysis, and there was no difference in postoperative wound infection rate between short-course and long-course groups (7.5% versus 7.1%, P = 0.912)., Conclusions: Standardization of postoperative antibiotic duration was associated with a decrease antibiotic duration without an increase in the incidence of wound infections after closure of dog bite wounds. This study highlights the feasibility of multidisciplinary standardization of pediatric trauma care across specialties and the safety of minimizing antibiotic duration after pediatric dog bite repairs., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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39. Uncertainty Profiles and Treatment Preferences for Intraductal Papillary Mucinous Neoplasms.
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Amara D, Sharma AR, Hewitt DB, Bridges JFP, Javed AA, Braithwaite RS, Wolfgang C, and Sacks GD
- Subjects
- Humans, Middle Aged, Female, Male, Uncertainty, Aged, Cross-Sectional Studies, Adult, Pancreatic Intraductal Neoplasms psychology, Pancreatic Intraductal Neoplasms therapy, Pancreatic Intraductal Neoplasms surgery, Watchful Waiting statistics & numerical data, Patient Preference statistics & numerical data, Patient Preference psychology, Pancreatic Neoplasms psychology, Pancreatic Neoplasms therapy, Pancreatic Neoplasms surgery
- Abstract
Introduction: Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic premalignant lesions frequently detected incidentally. Choosing between surgery and surveillance for IPMNs is rooted in uncertainty. We characterized patient preferences in IPMN management, and examined associations with patients' uncertainty profiles (risk perception, risk attitude, and uncertainty tolerance)., Methods: We conducted a cross-sectional survey drawn from a national opt-in panel. We simulated an encounter following an incidental computed tomography scan finding of an IPMN with a 5% cancer risk. We elicited participants' preferred treatment (surgery versus surveillance). Participant cancer risk perception, risk attitude (risk seeking versus risk averse), and uncertainty tolerance (comfort with the unknown) were determined using validated measures. Multivariate regression models assessed for independent predictors of treatment preference and risk perception., Results: The sample included 520 participants, ages 40-70, racially representative of the US population. Participants preferred surveillance (n = 331, 64%) over surgery (n = 189, 36%). Patients were significantly more likely to prefer surgery as their cancer risk perception increased (absolute difference = 12% from 1.0 standard deviation below to 1.0 standard deviation above the mean, 95% CI 3.5-20.2). Treatment preference was not significantly associated with risk attitude (P = 0.068) or uncertainty tolerance (P = 0.755). However, initial cancer risk perception was significantly associated with both uncertainty tolerance (P = 0.013) and baseline cancer anxiety (risk perception 16.4% versus 65%, not worried at all versus extremely worried, P < 0.001)., Conclusions: Patient preference varies widely for IPMN and is significantly associated with cancer risk perception, which is, in turn, significantly associated with uncertainty tolerance and cancer anxiety. These findings argue for the preference-sensitive nature of IPMN treatment decisions., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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40. Augmented reality for point-of-care ultrasound-guided vascular access in pediatric patients using Microsoft HoloLens 2: a preliminary evaluation.
- Author
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Zhang G, Nguyen TN, Fooladi-Talari H, Salvador T, Thomas K, Crowley D, Dingeman RS, and Shekhar R
- Abstract
Significance: Conventional ultrasound-guided vascular access procedures are challenging due to the need for anatomical understanding, precise needle manipulation, and hand-eye coordination. Recently, augmented reality (AR)-based guidance has emerged as an aid to improve procedural efficiency and potential outcomes. However, its application in pediatric vascular access has not been comprehensively evaluated., Aim: We developed an AR ultrasound application, HoloUS, using the Microsoft HoloLens 2 to display live ultrasound images directly in the proceduralist's field of view. We presented our evaluation of the effect of using the Microsoft HoloLens 2 for point-of-care ultrasound (POCUS)-guided vascular access in 30 pediatric patients., Approach: A custom software module was developed on a tablet capable of capturing the moving ultrasound image from any ultrasound machine's screen. The captured image was compressed and sent to the HoloLens 2 via a hotspot without needing Internet access. On the HoloLens 2, we developed a custom software module to receive, decompress, and display the live ultrasound image. Hand gesture and voice command features were implemented for the user to reposition, resize, and change the gain and the contrast of the image. We evaluated 30 (15 successful control and 12 successful interventional) cases completed in a single-center, prospective, randomized study., Results: The mean overall rendering latency and the rendering frame rate of the HoloUS application were 139.30 ms ( σ = 32.02 ms ) and 30 frames per second, respectively. The average procedure completion time was 17.3% shorter using AR guidance. The numbers of puncture attempts and needle redirections were similar between the two groups, and the number of head adjustments was minimal in the interventional group., Conclusion: We presented our evaluation of the results from the first study using the Microsoft HoloLens 2 that investigates AR-based POCUS-guided vascular access in pediatric patients. Our evaluation confirmed clinical feasibility and potential improvement in procedural efficiency., (© 2024 Society of Photo-Optical Instrumentation Engineers (SPIE).)
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- 2024
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41. Haptoglobin phenotype and levels in type 2 diabetes and effects of fenofibrate.
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Januszewski AS, Young HK, Ong KL, Li L, O'Connell RL, Lyons TJ, Kelly C, Zaharieva DP, Sullivan DR, Scott RS, Keech AC, and Jenkins AJ
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- Humans, Male, Female, Middle Aged, Aged, Fenofibrate therapeutic use, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 blood, Haptoglobins, Phenotype, Hypolipidemic Agents therapeutic use
- Abstract
Aims/hypothesis: In diabetes haptoglobin (Hp) 2 vs Hp 1 allelic product is associated with cardiac and renal complications. Few studies report both Hp phenotype and Hp levels. In a Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial substudy we evaluated the Hp phenotype, Hp levels, and fenofibrate effects., Materials and Methods: In 480 adults with type 2 diabetes (T2D) the Hp phenotype was assessed and the Hp level quantified (both using ELISAs assays) in plasma from baseline, after 6 weeks of fenofibrate, and (in n = 200) at 2 years post-randomization to fenofibrate or placebo., Results: The Hp phenotypes 1-1, 2-1, and 2-2 frequencies were 15%, 49%, and 36%, respectively. Baseline Hp levels differed by phenotype (P < 0.0001) and decreased (median 21%) after 6 weeks fenofibrate in all phenotypes (adjusted mean (95% CI): -0.27 (-0.32, -0.23) mg/mL in Hp 1-1, -0.29 (-0.31, -0.27) mg/mL in Hp 2-1 and -0.05 (-0.07, -0.02) mg/mL in Hp 2-2 (P = 0.005 and P = 0.055 vs Hp 1-1 and Hp 2-1, respectively)). At 2 years post-randomization the Hp levels in the placebo group had returned to baseline, whilst the fenofibrate-group levels remained similar to the 6 week levels., Conclusions: In type 2 diabetes, Hp levels differ by Hp phenotype and are decreased by fenofibrate in all phenotypes, but the effect is diminished in Hp 2-2., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)
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- 2024
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42. Histological improvements following energy restriction and exercise: The role of insulin resistance in resolution of MASH.
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Mucinski JM, Salvador AF, Moore MP, Fordham TM, Anderson JM, Shryack G, Cunningham RP, Lastra G, Gaballah AH, Diaz-Arias A, Ibdah JA, Rector RS, and Parks EJ
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- Humans, Male, Female, Middle Aged, Liver metabolism, Liver physiopathology, Liver pathology, Adult, Caloric Restriction methods, Fatty Liver therapy, Fatty Liver physiopathology, Exercise physiology, Exercise Therapy methods, Body Composition physiology, Treatment Outcome, Insulin Resistance physiology
- Abstract
Background & Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common liver diseases worldwide and is characterized by multi-tissue insulin resistance. The effects of a 10-month energy restriction and exercise intervention on liver histology, anthropometrics, plasma biochemistries, and insulin sensitivity were compared to standard of care (control) to understand mechanisms that support liver health improvements., Methods: Following medical diagnosis of MASH, individuals were randomized to treatment (n = 16) or control (n = 8). Liver fat (magnetic resonance spectroscopy), 18-hour plasma biochemical measurements, and isotopically labeled hyperinsulinemic-euglycemic clamps were completed pre- and post-intervention. Body composition and cardiorespiratory fitness (VO
2 peak) were also measured mid-intervention. Those in the treatment group were counseled to reduce energy intake and completed supervised, high-intensity interval training (3x/week) for 10 months. Controls continued physician-directed care., Results: Treatment induced significant (p <0.05) reductions in body weight, fat mass, and liver injury, while VO2 peak (p <0.05) and non-esterified fatty acid suppression (p = 0.06) were improved. Both groups exhibited reductions in total energy intake, hemoglobin A1c, hepatic insulin resistance, and liver fat (p <0.05). Compared to control, treatment induced a two-fold increase in peripheral insulin sensitivity which was significantly related to higher VO2 peak and resolution of liver disease., Conclusions: Exercise and energy restriction elicited significant and clinically meaningful treatment effects on liver health, potentially driven by a redistribution of excess nutrients to skeletal muscle, thereby reducing hepatic nutrient toxicity. Clinical guidelines should emphasize the addition of aerobic exercise in lifestyle treatments for the greatest histologic benefit in individuals with advanced MASH., Impact and Implications: The mechanisms that underpin histologic improvement in individuals with metabolic dysfunction-associated steatohepatitis (MASH) are not well understood. This study evaluated the relationship between liver and metabolic health, testing how changes in one may affect the other. We investigated the effects of energy restriction and exercise on the association between multi-tissue insulin sensitivity and histologic improvements in participants with biopsy-proven MASH. For the first time, these results show that an improvement in peripheral (but not hepatic) insulin sensitivity and systemic markers of muscle function (i.e. cardiorespiratory fitness) were strongly related to resolution of liver disease. Extrahepatic disposal of substrates and improved fitness levels supported histologic improvement, confirming the addition of exercise as crucial to lifestyle interventions in MASH., Clinical Trial Number: NCT03151798., (Copyright © 2024 European Association for the Study of the Liver. All rights reserved.)- Published
- 2024
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43. Progression of hypertensive disorders of pregnancy during induction of labor in term nulliparous patients.
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Perelman AD, Braithwaite RS, Caughey AB, Marty LN, Hirschberg CI, Pass AR, and Penfield CA
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- 2024
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44. Association of Initiation of Statewide Pediatric Trauma Collaborative and Hospital Preventable Transfer Rates.
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Scaife JH, Clinker CE, Alexander AJ, Iantorno SE, Eldredge RS, Swendiman RA, Fenton SJ, and Russell KW
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Introduction: The Utah Pediatric Trauma Network (UPTN), established in 2019, is a collaboration of hospitals that have implemented guidelines to optimize pediatric trauma care. The purpose of this study was to determine whether preventable transfer (PT) rates decreased following the establishment of the UTPN and what hospital characteristics were associated with decreased preventable transfers., Methods: Children with traumatic injuries transferred from hospitals in the UPTN to the state's only Level I Pediatric Trauma Center between 2013 and 2023 were retrospectively analyzed. A PT was a child discharged within 48 h of arrival without surgical intervention or advanced imaging studies. The main hospital-level outcome measure was an overall decrease in PT after the UPTN establishment in 2019., Results: After 2019, 34 of the 46 hospitals meeting inclusion criteria saw a decrease in the percentage of PTs, while 12 saw an increase in PT rate, with an overall median change of -7 % (IQR -14 %, 0 %). We observed that hospitals with decreased PT had higher rates of PT before the establishment of the UPTN and had higher overall transfer volume than hospitals without a decreased PT rate. Can we put the overall p value in this?, Conclusion: Most hospitals were able to successfully decrease PT rates following the creation of the UPTN. More smaller hospitals did not successfully decrease PT, so more work may need to be done to target lower-volume hospitals., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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45. Tributyltin Enhances Macrophage Inflammation and Lipolysis, Contributing to Adipose Tissue Dysfunction.
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Chang RC, Whitlock RS, Joloya E, To KT, Huang Y, and Blumberg B
- Abstract
Tributyltin (TBT) is a synthetic chemical widely used in industrial and commercial applications. TBT exposure has been proven to elicit obesogenic effects. Gestational exposure led to increased white adipose tissue depot size in exposed (F1, F2) animals and in unexposed generations (F3, F4), an example of transgenerational inheritance. TBT exerts these effects in part by increasing the number and size of white adipocytes, altering the fate of multipotent mesenchymal stromal stem cells to favor the adipocyte lineage, altering adipokine secretion, and modulating chromatin structure. Adipose tissue resident macrophages are critical regulators in adipose tissue; however, the effects of TBT on adipose tissue macrophages remained unclear. Here we investigated the effects of TBT on macrophages and consequent impacts on adipocyte function. TBT significantly enhanced palmitate-induced inflammatory gene expression in mouse bone marrow derived macrophages and this effect was attenuated by the antagonizing action of the nuclear receptor peroxisome proliferator activated receptor gamma. TBT-treated macrophages decreased lipid accumulation in white adipocytes differentiated from mesenchymal stromal stem cells accompanied by increased expression of lipolysis genes. Lastly, ancestral TBT exposure increased Tnf expression in adipose tissue resident macrophages in both exposed (F2) and unexposed (F3) generations, suggesting that TBT exposure led to an inherited predisposition toward inflammatory adipose tissue macrophages that can manipulate adipose tissue function. These findings provide new insights into the interplay between adipocytes and adipose tissue macrophages in obesity, further establishing a role for obesogens such as TBT in the development of obesity-related metabolic disorders., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2024
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46. 3D printed microfluidic devices with electrodes for electrochemical analysis.
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Selemani MA, Cenhrang K, Azibere S, Singhateh M, and Martin RS
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A review with 93 references describing various 3D printing approaches that have been used to create microfluidic devices containing electrodes for electrochemical detection. The use of 3D printing to fabricate microfluidic devices is a rapidly growing area. One significant research area is how to detect analytes in the devices for quantitation purposes. This review article is focused on methods used to integrate electrodes into the devices for electrochemical detection. The review is organized in terms of the methodology for integrating the electrode within the device. This includes (1) external coupling of traditional electrode materials with 3D printed devices; (2) printing conductive electrode materials as part of device printing; and (3) integrating traditional electrodes into the device as part of the print process. Example applications are given and some future directions are also outlined.
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- 2024
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47. Epstein-Barr virus replication within differentiated epithelia requires pRb sequestration of activator E2F transcription factors.
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Schaal DL, Amucheazi AA, Jones SC, Nkadi EH, and Scott RS
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- Humans, Cell Differentiation, Papillomavirus E7 Proteins metabolism, Papillomavirus E7 Proteins genetics, Epstein-Barr Virus Infections virology, Epstein-Barr Virus Infections metabolism, Epstein-Barr Virus Infections genetics, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Epithelial Cells virology, Epithelial Cells metabolism, Papillomavirus Infections virology, Papillomavirus Infections metabolism, Papillomavirus Infections genetics, Human papillomavirus 16 physiology, Human papillomavirus 16 genetics, Human papillomavirus 16 metabolism, Herpesvirus 4, Human physiology, Herpesvirus 4, Human genetics, Herpesvirus 4, Human metabolism, Virus Replication, Keratinocytes virology, Keratinocytes metabolism, Retinoblastoma Protein metabolism, Retinoblastoma Protein genetics, E2F Transcription Factors metabolism, E2F Transcription Factors genetics
- Abstract
Epstein-Barr virus (EBV) co-infections with human papillomavirus (HPV) have been observed in oropharyngeal squamous cell carcinoma. Modeling EBV/HPV co-infection in organotypic epithelial raft cultures revealed that HPV16 E7 inhibited EBV productive replication through the facilitated degradation of the retinoblastoma protein pRb/p105. To further understand how pRb is required for EBV productive replication, we generated CRISPR-Cas9 pRb knockout (KO) normal oral keratinocytes (NOKs) in the context of wild-type and mutant K120E p53. EBV replication was examined in organotypic rafts as a physiological correlate for epithelial differentiation. In pRb KO rafts, EBV DNA copy number was statistically decreased compared to vector controls, regardless of p53 context. Loss of pRb did not affect EBV binding or internalization of calcium-treated NOKs or early infection of rafts. Rather, the block in EBV replication correlated with impaired immediate early gene expression. An EBV infection time course in rafts with mutant p53 demonstrated that pRb-positive basal cells were initially infected with delayed replication occurring in differentiated layers. Loss of pRb showed increased S-phase progression makers and elevated activator E2F activity in raft tissues. Complementation with a panel of pRb/E2F binding mutants showed that wild type or pRb∆685 mutant capable of E2F binding reduced S-phase marker gene expression, rescued EBV DNA replication, and restored BZLF1 expression in pRb KO rafts. However, pRb KO complemented with pRb661W mutant, unable to bind E2Fs, failed to rescue EBV replication in raft culture. These findings suggest that EBV productive replication in differentiated epithelium requires pRb inhibition of activator E2Fs to restrict S-phase progression.IMPORTANCEA subset of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma is co-positive for Epstein-Barr virus (EBV). Potential oncogenic viral interactions revealed that HPV16 E7 inhibited productive EBV replication within the differentiated epithelium. As E7 mediates the degradation of pRb, we aimed to establish how pRb is involved in EBV replication. In the context of differentiated epithelium using organotypic raft culture, we evaluated how the loss of pRb affects EBV lytic replication to better comprehend EBV contributions to carcinogenesis. In this study, ablation of pRb interfered with EBV replication at the level of immediate early gene expression. Loss of pRb increased activator E2Fs and associated S-phase gene expression throughout the differentiated epithelium. Complementation studies showed that wild type and pRb mutant capable of binding to E2F rescued EBV replication, while pRb mutant lacking E2F binding did not. Altogether, these studies support that in differentiated tissues, HPV16 E7-mediated degradation of pRb inhibits EBV replication through unregulated E2F activity., Competing Interests: The authors declare no conflict of interest.
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- 2024
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48. Cost-effectiveness of screening and treating alcohol use and depression among people living with HIV in Zimbabwe: a mathematical modeling study.
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Su JI, Yeo YR, Jeetoo M, Morojele NK, Francis JM, Shenoi S, and Braithwaite RS
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- Humans, Zimbabwe epidemiology, Alcoholism therapy, Alcoholism epidemiology, Alcoholism complications, Male, Female, Quality-Adjusted Life Years, Adult, Depressive Disorder, Major epidemiology, Depressive Disorder, Major economics, Cost-Benefit Analysis, HIV Infections epidemiology, HIV Infections economics, HIV Infections complications, Models, Theoretical, Mass Screening economics, Mass Screening methods
- Abstract
Background: Alcohol use disorder (AUD) and major depressive disorder (MDD) drive HIV transmission in many sub-Saharan African settings. The impact of screening and treating AUD and MDD on HIV outcomes is unknown. We aimed to identify the cost-effectiveness of AUD and MDD interventions in Zimbabwe, and their potential contribution to reaching Zimbabwe's Ending the HIV Epidemic 2030 goal., Methods: Using a validated HIV compartmental transmission model in Zimbabwe, we compared four policy scenarios: prevention as usual (baseline); implement AUD screening (using AUDIT) and treatment (motivational interviewing and cognitive-behavioral therapy); implement MDD screening (using PHQ-9) and treatment (cognitive-behavioral therapy); and implement screening and treatment for both. Outcomes were HIV incidence projections, infections averted through 2030, quality-adjusted life-years gained, cost per infection averted, and cost per QALY gained. Analyses considered "spillover," when treatment for AUD also results in an improvement in MDD and the converse. Sensitivity analyses identified cost reductions necessary for AUD and MDD interventions to be as cost-effective as other HIV interventions, particularly the scale-up of long-acting PrEP., Results: AUD and MDD combined will be responsible for 21.1% of new HIV infections in Zimbabwe by 2030. Without considering spillover, compared to the baseline, MDD intervention can reduce new infections by 5.4% at $2039/infection averted and $3186/QALY. AUD intervention can reduce new infections by 5.8%, but at $2,968/infection averted and $4753/QALY, compared to baseline. Both MDD and AUD interventions can reduce new infections by 11.1% at $2810/infection averted and $4229/QALY, compared to baseline. Considering spillover, compared to the baseline, MDD intervention can reduce new infections by 6.4% at $1714/infection averted and $2630/QALY. AUD intervention can reduce new infections by 7.4%, but at $2299/infection averted and $3560/QALY compared to baseline. Both MDD and AUD interventions can reduce new infections by 11.9% at $2247/infection averted and $3382/QALY compared to baseline. For MDD intervention to match the cost-effectiveness of scaling long-acting PrEP, the cost of MDD intervention would need to be reduced from $16.64 to $12.88 per person., Conclusions: Implementing AUD and MDD interventions can play an important role in HIV reduction in Zimbabwe, particularly if intervention cost can be decreased while preserving effectiveness., (© 2024. The Author(s).)
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- 2024
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49. Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial.
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Wright RS, Raal FJ, Koenig W, Landmesser U, Leiter LA, Vikarunnessa S, Lesogor A, Maheux P, Talloczy Z, Zang X, Schwartz GG, and Ray KK
- Subjects
- Humans, Male, Middle Aged, Female, Treatment Outcome, Aged, Time Factors, Anticholesteremic Agents adverse effects, Anticholesteremic Agents therapeutic use, Anticholesteremic Agents administration & dosage, Down-Regulation, PCSK9 Inhibitors, Proprotein Convertase 9, RNA, Small Interfering, Cholesterol, LDL blood, Biomarkers blood, Hyperlipoproteinemia Type II blood, Hyperlipoproteinemia Type II drug therapy, Hyperlipoproteinemia Type II diagnosis, Hyperlipoproteinemia Type II genetics
- Abstract
Aims: Data describing the long-term efficacy and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials., Methods and Results: Following completion of the parent trial, adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent, or heterozygous familial hypercholesterolaemia received open-label inclisiran twice yearly (after initial and 3-month doses) until Day 990, followed by an end-of-study visit at Day 1080 or ≥ 90 days after the last dose. The study endpoints included the proportion of patients achieving pre-specified low-density lipoprotein cholesterol (LDL-C) goals [ASCVD: < 1.8 mmol/L (< 70 mg/dL); ASCVD risk equivalent: < 2.6 mmol/L (< 100 mg/dL)], percentage and absolute changes in LDL-C at end-of-study, and safety of inclisiran. Of 3274 patients, 2446 (74.7%) were followed until end-of-study. Mean age was 64.9 ± 9.9 years, 82.7% (n = 2709) had ASCVD, and mean baseline LDL-C was 2.9 ± 1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% [95% confidence interval (CI): 76.8, 80.0] of patients achieved pre-specified LDL-C goals and mean percentage change in LDL-C was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at injection site (all mild/moderate) occurred in 5.9% of the patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified., Conclusion: In the largest and longest follow-up to date with >12 000 patient-years exposure, inclisiran demonstrated consistent and effective LDL-C lowering with a favourable long-term safety and tolerability profile., Trial Registration Number: ClinicalTrials.gov identifier: NCT03814187., Competing Interests: Conflict of interest: R.S.W. reports receiving advisory board fees from Boehringer Ingelheim and past fees for consulting on lipid issues with The Medicines Company; F.J.R. reports receiving advisory board fees and lecture fees from Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, Novartis, and LIB Therapeutics; W.K. reports receiving consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen; consulting fees from Pfizer, The Medicines Company, Novartis, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, Esperion, Genentech, OMEICOS, Novo Nordisk, LIB Therapeutics, Daiichi Sankyo, New Amsterdam Pharma, and TenSixteen Bio; lecture fees from Berlin-Chemie, Bristol-Myers Squibb, and Sanofi; and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr Beckmann Pharma; U.L. reports receiving grant support from Amgen, Bayer, and Novartis and advisory board fee from Novartis; L.A.L. reports grant support paid to his institution and advisory board fees and fees for CME from Amgen and Novartis; grant support paid to his institution and fees for serving on a steering committee from Kowa, The Medicines Company and Novartis; and advisory board fees and fees for CME from Amarin, AstraZeneca, HLS, Merck, New Amsterdam, Pfizer, and Sanofi; G.G.S. reports receiving research support paid to his institution from AstraZeneca, Sanofi, Silence Therapeutics, and The Medicines Company and a patent (62/806313) on a method for reducing cardiovascular risk assigned in full to the University of Colorado; K.K.R. reports receiving support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre; his institution (Imperial College London) receives support from the NIHR Applied Research Collaboration Northwest London. K.K.R. also reports receiving lecture fees from Aegerion Pharmaceuticals, Kowa, Cipla, Algorithm, and Zuelling Pharma; grant support paid to his institution; lecture fees and advisory board fees from Amgen, Regeneron Pharmaceuticals/Sanofi, and Pfizer; lecture fees and fees for serving on steering committees for trials from AstraZeneca and Eli Lilly; fees for serving on steering committees for trials from Cerenis Therapeutics, The Medicines Company, and Esperion; advisory board fees from Akcea Therapeutics, Novartis, Silence Therapeutics, Bayer, and Daiichi Sankyo; lecture fees and advisory board fees from Takeda, Boehringer Ingelheim, and Dr Reddy’s Laboratories; grant support and advisory board fees from Merck Sharp & Dohme; fees for serving on a clinical events adjudication committee from AbbVie; and fees for serving as principal investigator for a trial from Resverlogix; Z.T., S.V., and X.Z. are all employees of Novartis Pharmaceuticals Corp, East Hanover, New Jersey, USA and hold shares in Novartis; A.L. is employee of Novartis Pharma AG, Basel, Switzerland; P.M. was an employee of Novartis Pharma AG, Basel, Switzerland, at the time of conducting this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2024
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50. Proteomics Analysis on the Effects of Oxidative Stress and Antioxidants on Proteins Involved in Sterol Transport and Metabolism in Human Telomerase Transcriptase-Overexpressing-Retinal Pigment Epithelium Cells.
- Author
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Duncan RS, Keightley A, Lopez AA, Hall CW, and Koulen P
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- Humans, Biological Transport drug effects, Cell Line, Tocopherols pharmacology, Tocopherols metabolism, Retinal Pigment Epithelium metabolism, Retinal Pigment Epithelium drug effects, Oxidative Stress drug effects, Proteomics methods, Telomerase metabolism, Telomerase genetics, Antioxidants metabolism, Antioxidants pharmacology, Sterols metabolism, Sterols pharmacology
- Abstract
Age-related macular degeneration (AMD) is the most prevalent ocular disease in the elderly, resulting in blindness. Oxidative stress plays a role in retinal pigment epithelium (RPE) pathology observed in AMD. Tocopherols are potent antioxidants that prevent cellular oxidative damage and have been shown to upregulate the expression of cellular antioxidant proteins. Here, we determined whether oxidative stress and tocopherols, using either normal cellular conditions or conditions of sublethal cellular oxidative stress, alter the expression of proteins mediating sterol uptake, transport, and metabolism. Human telomerase transcriptase-overexpressing RPE cells (hTERT-RPE) were used to identify differential expression of proteins resulting from treatments. We utilized a proteomics strategy to identify protein expression changes in treated cells. After the identification and organization of data, we divided the identified proteins into groups related to biological function: cellular sterol uptake, sterol transport and sterol metabolism. Exposure of cells to conditions of oxidative stress and exposure to tocopherols led to similar protein expression changes within these three groups, suggesting that α-tocopherol (αT) and γ-tocopherol (γT) can regulate the expression of sterol uptake, transport and metabolic proteins in RPE cells. These data suggest that proteins involved in sterol transport and metabolism may be important for RPE adaptation to oxidative stress, and these proteins represent potential therapeutic targets.
- Published
- 2024
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