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2. Die intravesikale Applikation von BCG induziert eine angeborene Immunreaktionen gegen SARS-CoV-2 beim Urothelkarzinom: Eine Premiere

Author

Pichler, R, Diem, G, Hackl, H, Koutnik, J, Mertens, LS, D'Andrea, D, Pradere, B, Soria, F, Mari, A, Laukhtina, E, Krajewski, W, Yuen-Chun Teoh, J, Del Guidice, F, Moschini, M, Thurnher, M, Posch, W, Pichler, R, Diem, G, Hackl, H, Koutnik, J, Mertens, LS, D'Andrea, D, Pradere, B, Soria, F, Mari, A, Laukhtina, E, Krajewski, W, Yuen-Chun Teoh, J, Del Guidice, F, Moschini, M, Thurnher, M, and Posch, W

Published
2023

12. Major lipids, apolipoproteins, and risk of vascular disease

Author

Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, Wood AM, Lewington S, Sattar N, Packard CJ, Collins R, Thompson SG, Tipping RW, Ford CE, Pressel SL, Walldius G, Jungner I, Folsom AR, Chambless LE, Panagiotakos DB, Pitsavos C, Chrysohoou C, Stefanadis C, Knuiman M, Goldbourt U, Benderly M, Tanne D, Whincup PH, Wannamethee SG, Morris RW, Kiechl S, Willeit J, Santer P, Mayr A, Wald N, Ebrahim S, Lawlor DA, Yarnell JW, Gallacher J, Casiglia E, Tikhonoff V, Nietert PJ, Sutherland SE, Bachman DL, Keil JE, Cushman M, Psaty BM, Tracy RP, Tybjaerg Hansen A, Nordestgaard BG, Benn M, Frikke Schmidt R, Giampaoli S, Palmieri L, Vanuzzo D, Pilotto L, Gómez de la Cámara A, Gómez Gerique JA, Simons L, McCallum J, Friedlander Y, Fowkes FG, Lee AJ, Smith FB, Taylor J, Guralnik JM, Phillips CL, Wallace R, Guralnik J, Blazer DG, Khaw KT, Brenner H, Raum E, Müller H, Rothenbacher D, Jansson JH, Wennberg P, Nissinen A, Donfrancesco C, Salomaa V, Harald K, Jousilahti P, Vartiainen E, Woodward M, D'Agostino RB, Wolf PA, Vasan RS, Pencina MJ, Bladbjerg EM, Jørgensen T, Møller L, Jespersen J, Dankner R, Chetrit A, Lubin F, Rosengren A, Wilhelmsen L, Lappas G, Eriksson H, Björkelund C, Lissner L, Bengtsson C, Cremer P, Nagel D, Tilvis RS, Strandberg TE, Rodriguez B, Dekker JM, Nijpels G, Stehouwer CD, Rimm E, Pai JK, Sato S, Iso H, Kitamura A, Noda H, Salonen JT, Nyyssönen K, Tuomainen TP, Deeg DJ, Poppelaars JL, Meade TW, Cooper JA, Hedblad B, Berglund G, Engstrom G, Verschuren WM, Blokstra A, Döring A, Koenig W, Meisinger C, Mraz W, Verschure WM, Bas Bueno de Mesquita H, Kuller LH, Grandits G, Selmer R, Tverdal A, Nystad W, Gillum R, Mussolino M, Hankinson S, Manson J, Knottenbelt C, Bauer KA, Naito Y, Holme I, Nakagawa H, Miura K, Ducimetiere P, Jouven X, Crespo CJ, Garcia Palmieri MR, Amouyel P, Arveiler D, Evans A, Ferrieres J, Schulte H, Assmann G, Shepherd J, Ford I, Cantin B, Lamarche B, Després JP, Dagenais GR, Barrett Connor E, Wingard DL, Bettencourt R, Gudnason V, Aspelund T, Sigurdsson G, Thorsson B, Trevisan M, Witteman J, Kardys I, Breteler M, Hofman A, Tunstall Pedoe H, Tavendale R, Lowe GD, Howard BV, Zhang Y, Best L, Umans J, Ben Shlomo Y, Davey Smith G, Onat A, Njølstad I, Mathiesen EB, Løchen ML, Wilsgaard T, Ingelsson E, Lind L, Giedraitis V, Lannfelt L, Gaziano JM, Stampfer M, Ridker P, Ulmer H, Diem G, Concin H, Tosetto A, Rodeghiero F, Marmot M, Clarke R, Fletcher A, Brunner E, Shipley M, Buring J, Cobbe SM, Robertson M, He Y, Marin Ibañez A, Feskens EJ, Kromhout D, Walker M, Watson S, Erqou S, Orfei L, Pennells L, Perry PL, Alexander M, Wensley F, White IR, Danesh J., PANICO, SALVATORE, Developmental Genetics, EMGO+ - Lifestyle, Overweight and Diabetes, Epidemiology and Data Science, General practice, Psychiatry, EMGO - Lifestyle, overweight and diabetes, Emerging Risk Factors, Collaboration, Di Angelantonio, E, Sarwar, N, Perry, P, Kaptoge, S, Ray, Kk, Thompson, A, Wood, Am, Lewington, S, Sattar, N, Packard, Cj, Collins, R, Thompson, Sg, Tipping, Rw, Ford, Ce, Pressel, Sl, Walldius, G, Jungner, I, Folsom, Ar, Chambless, Le, Panagiotakos, Db, Pitsavos, C, Chrysohoou, C, Stefanadis, C, Knuiman, M, Goldbourt, U, Benderly, M, Tanne, D, Whincup, Ph, Wannamethee, Sg, Morris, Rw, Kiechl, S, Willeit, J, Santer, P, Mayr, A, Wald, N, Ebrahim, S, Lawlor, Da, Yarnell, Jw, Gallacher, J, Casiglia, E, Tikhonoff, V, Nietert, Pj, Sutherland, Se, Bachman, Dl, Keil, Je, Cushman, M, Psaty, Bm, Tracy, Rp, Tybjaerg Hansen, A, Nordestgaard, Bg, Benn, M, Frikke Schmidt, R, Giampaoli, S, Palmieri, L, Panico, Salvatore, Vanuzzo, D, Pilotto, L, Gómez de la Cámara, A, Gómez Gerique, Ja, Simons, L, Mccallum, J, Friedlander, Y, Fowkes, Fg, Lee, Aj, Smith, Fb, Taylor, J, Guralnik, Jm, Phillips, Cl, Wallace, R, Guralnik, J, Blazer, Dg, Khaw, Kt, Brenner, H, Raum, E, Müller, H, Rothenbacher, D, Jansson, Jh, Wennberg, P, Nissinen, A, Donfrancesco, C, Salomaa, V, Harald, K, Jousilahti, P, Vartiainen, E, Woodward, M, D'Agostino, Rb, Wolf, Pa, Vasan, R, Pencina, Mj, Bladbjerg, Em, Jørgensen, T, Møller, L, Jespersen, J, Dankner, R, Chetrit, A, Lubin, F, Rosengren, A, Wilhelmsen, L, Lappas, G, Eriksson, H, Björkelund, C, Lissner, L, Bengtsson, C, Cremer, P, Nagel, D, Tilvis, R, Strandberg, Te, Rodriguez, B, Dekker, Jm, Nijpels, G, Stehouwer, Cd, Rimm, E, Pai, Jk, Sato, S, Iso, H, Kitamura, A, Noda, H, Salonen, Jt, Nyyssönen, K, Tuomainen, Tp, Deeg, Dj, Poppelaars, Jl, Meade, Tw, Cooper, Ja, Hedblad, B, Berglund, G, Engstrom, G, Verschuren, Wm, Blokstra, A, Döring, A, Koenig, W, Meisinger, C, Mraz, W, Verschure, Wm, Bas Bueno de Mesquita, H, Kuller, Lh, Grandits, G, Selmer, R, Tverdal, A, Nystad, W, Gillum, R, Mussolino, M, Hankinson, S, Manson, J, Knottenbelt, C, Bauer, Ka, Naito, Y, Holme, I, Nakagawa, H, Miura, K, Ducimetiere, P, Jouven, X, Crespo, Cj, Garcia Palmieri, Mr, Amouyel, P, Arveiler, D, Evans, A, Ferrieres, J, Schulte, H, Assmann, G, Shepherd, J, Ford, I, Cantin, B, Lamarche, B, Després, Jp, Dagenais, Gr, Barrett Connor, E, Wingard, Dl, Bettencourt, R, Gudnason, V, Aspelund, T, Sigurdsson, G, Thorsson, B, Trevisan, M, Witteman, J, Kardys, I, Breteler, M, Hofman, A, Tunstall Pedoe, H, Tavendale, R, Lowe, Gd, Howard, Bv, Zhang, Y, Best, L, Umans, J, Ben Shlomo, Y, Davey Smith, G, Onat, A, Njølstad, I, Mathiesen, Eb, Løchen, Ml, Wilsgaard, T, Ingelsson, E, Lind, L, Giedraitis, V, Lannfelt, L, Gaziano, Jm, Stampfer, M, Ridker, P, Ulmer, H, Diem, G, Concin, H, Tosetto, A, Rodeghiero, F, Marmot, M, Clarke, R, Fletcher, A, Brunner, E, Shipley, M, Buring, J, Cobbe, Sm, Robertson, M, He, Y, Marin Ibañez, A, Feskens, Ej, Kromhout, D, Walker, M, Watson, S, Erqou, S, Orfei, L, Pennells, L, Perry, Pl, Alexander, M, Wensley, F, White, Ir, and Danesh, J.

Subjects
medicine.medical_specialty, Apolipoprotein B, biology, Triglyceride, business.industry, Vascular disease, Cholesterol, Proportional hazards model, Hazard ratio, Context (language use), General Medicine, 11 Medical And Health Sciences, medicine.disease, Gastroenterology, Article, chemistry.chemical_compound, Endocrinology, chemistry, Internal medicine, General & Internal Medicine, biology.protein, Medicine, lipids (amino acids, peptides, and proteins), Myocardial infarction, business
Abstract

Udgivelsesdato: 2009-Nov-11 CONTEXT: Associations of major lipids and apolipoproteins with the risk of vascular disease have not been reliably quantified. OBJECTIVE: To assess major lipids and apolipoproteins in vascular risk. DESIGN, SETTING, AND PARTICIPANTS: Individual records were supplied on 302,430 people without initial vascular disease from 68 long-term prospective studies, mostly in Europe and North America. During 2.79 million person-years of follow-up, there were 8857 nonfatal myocardial infarctions, 3928 coronary heart disease [CHD] deaths, 2534 ischemic strokes, 513 hemorrhagic strokes, and 2536 unclassified strokes. MAIN OUTCOME MEASURES: Hazard ratios (HRs), adjusted for several conventional factors, were calculated for 1-SD higher values: 0.52 log(e) triglyceride, 15 mg/dL high-density lipoprotein cholesterol (HDL-C), 43 mg/dL non-HDL-C, 29 mg/dL apolipoprotein AI, 29 mg/dL apolipoprotein B, and 33 mg/dL directly measured low-density lipoprotein cholesterol (LDL-C). Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. RESULTS: The rates of CHD per 1000 person-years in the bottom and top thirds of baseline lipid distributions, respectively, were 2.6 and 6.2 with triglyceride, 6.4 and 2.4 with HDL-C, and 2.3 and 6.7 with non-HDL-C. Adjusted HRs for CHD were 0.99 (95% CI, 0.94-1.05) with triglyceride, 0.78 (95% CI, 0.74-0.82) with HDL-C, and 1.50 (95% CI, 1.39-1.61) with non-HDL-C. Hazard ratios were at least as strong in participants who did not fast as in those who did. The HR for CHD was 0.35 (95% CI, 0.30-0.42) with a combination of 80 mg/dL lower non-HDL-C and 15 mg/dL higher HDL-C. For the subset with apolipoproteins or directly measured LDL-C, HRs were 1.50 (95% CI, 1.38-1.62) with the ratio non-HDL-C/HDL-C, 1.49 (95% CI, 1.39-1.60) with the ratio apo B/apo AI, 1.42 (95% CI, 1.06-1.91) with non-HDL-C, and 1.38 (95% CI, 1.09-1.73) with directly measured LDL-C. Hazard ratios for ischemic stroke were 1.02 (95% CI, 0.94-1.11) with triglyceride, 0.93 (95% CI, 0.84-1.02) with HDL-C, and 1.12 (95% CI, 1.04-1.20) with non-HDL-C. CONCLUSION: Lipid assessment in vascular disease can be simplified by measurement of either total and HDL cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride.

Published
2016
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15. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis

Author

Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, Danesh JTipping RW, Ford CE, Pressel SL, Walldius G, Jungner I, Folsom AR, Chambless L, Ballantyne CM, Panagiotakos D, Pitsavos C, Chrysohoou C, Stefanadis C, Knuiman MW, Goldbourt U, Benderly M, Tanne D, Whincup P, Wannamethee SG, Morris RW, Kiechl S, Willeit J, Mayr A, Schett G, Wald N, Ebrahim S, Lawlor D, Yarnell J, Gallacher J, Casiglia E, Tikhonoff V, Nietert PJ, Sutherland SE, Bachman DL, Keil JE, Cushman M, Psaty BM, Tracy R, Tybjaerg Hansen A, Nordestgaard BG, Zacho J, Frikke Schmidt R, Giampaoli S, Palmieri L, Vanuzzo D, Pilotto L, de la Cámara AG, Gerique JA, Simons L, McCallum J, Friedlander Y, Fowkes FG, Lee A, Taylor J, Guralnik JM, Phillips CL, Wallace RB, Blazer DG, Khaw KT, Brenner H, Raum E, Müller H, Rothenbacher D, Jansson JH, Wennberg P, Nissinen A, Donfrancesco C, Salomaa V, Harald K, Jousilahti P, Vartiainen E, Woodward M, D'Agostino RB, Wolf PA, Vasan RS, Benjamin EJ, Bladbjerg EM, Jørgensen T, Møller L, Jespersen J, Dankner R, Chetrit A, Lubin F, Rosengren A, Wilhelmsen L, Lappas G, Eriksson H, Björkelund C, Lissner L, Bengtsson C, Cremer P, Nagel D, Tilvis RS, Strandberg TE, Kiyohara Y, Arima H, Doi Y, Ninomiya T, Rodriguez B, Dekker J, Nijpels G, Stehouwer CD, Rimm E, Pai JK, Sato S, Iso H, Kitamura A, Noda H, Salonen JT, Nyyssönen K, Tuomainen TP, Laukkanen JA, Deeg DJ, Bremmer MA, Meade TW, Cooper JA, Hedblad B, Berglund G, Engström G, Verschuren WM, Blokstra A, Shea S, Döring A, Koenig W, Meisinger C, Bueno de Mesquita HB, Kuller LH, Grandits G, Selmer R, Tverdal A, Nystad W, Gillum RF, Mussolino M, Hankinson S, Manson JE, Knottenbelt C, Bauer KA, Davidson K, Kirkland S, Shaffer J, Korin MR, Naito Y, Holme I, Nakagawa H, Miura K, Ducimetiere P, Jouven X, Luc G, Crespo CJ, Garcia Palmieri MR, Amouyel P, Arveiler D, Evans A, Ferrieres J, Schulte H, Assmann G, Packard CJ, Sattar N, Westendorp RG, Buckley BM, Cantin B, Lamarche B, Després JP, Dagenais GR, Barrett Connor E, Wingard DL, Bettencourt RR, Gudnason V, Aspelund T, Sigurdsson G, Thorsson B, Trevisan M, Witteman J, Kardys I, Breteler MM, Hofman A, Tunstall Pedoe H, Tavendale R, Howard BV, Zhang Y, Best L, Umans J, Ben Shlomo Y, Davey Smith G, Onat A, Njølstad I, Mathiesen EB, Løchen ML, Wilsgaard T, Ingelsson E, Basu S, Cederholm T, Byberg L, Gaziano JM, Stampfer M, Ridker PM, Ulmer H, Diem G, Concin H, Tosetto A, Rodeghiero F, Wassertheil Smoller S, Marmot IM, Clarke R, Fletcher A, Brunner E, Shipley M, Buring J, Shepherd J, Cobbe S, Ford I, Robertson M, He Y, Ibañez AM, Feskens EJ, Walker M, Watson S, Erqou S, Lewington S, Pennells L, Perry PL, Ray KK, Sarwar N, Alexander M, Thompson A, White IR, Wood AM, Danesh J., PANICO, SALVATORE, Interne Geneeskunde, MUMC+: MA Interne Geneeskunde (3), RS: CARIM School for Cardiovascular Diseases, General practice, EMGO - Lifestyle, overweight and diabetes, Psychiatry, EMGO - Mental health, Emerging Risk Factors, Collaboration, Kaptoge, S, Di Angelantonio, E, Lowe, G, Pepys, Mb, Thompson, Sg, Collins, R, Danesh JTipping, Rw, Ford, Ce, Pressel, Sl, Walldius, G, Jungner, I, Folsom, Ar, Chambless, L, Ballantyne, Cm, Panagiotakos, D, Pitsavos, C, Chrysohoou, C, Stefanadis, C, Knuiman, Mw, Goldbourt, U, Benderly, M, Tanne, D, Whincup, P, Wannamethee, Sg, Morris, Rw, Kiechl, S, Willeit, J, Mayr, A, Schett, G, Wald, N, Ebrahim, S, Lawlor, D, Yarnell, J, Gallacher, J, Casiglia, E, Tikhonoff, V, Nietert, Pj, Sutherland, Se, Bachman, Dl, Keil, Je, Cushman, M, Psaty, Bm, Tracy, R, Tybjaerg Hansen, A, Nordestgaard, Bg, Zacho, J, Frikke Schmidt, R, Giampaoli, S, Palmieri, L, Panico, Salvatore, Vanuzzo, D, Pilotto, L, de la Cámara, Ag, Gerique, Ja, Simons, L, Mccallum, J, Friedlander, Y, Fowkes, Fg, Lee, A, Taylor, J, Guralnik, Jm, Phillips, Cl, Wallace, Rb, Blazer, Dg, Khaw, Kt, Brenner, H, Raum, E, Müller, H, Rothenbacher, D, Jansson, Jh, Wennberg, P, Nissinen, A, Donfrancesco, C, Salomaa, V, Harald, K, Jousilahti, P, Vartiainen, E, Woodward, M, D'Agostino, Rb, Wolf, Pa, Vasan, R, Benjamin, Ej, Bladbjerg, Em, Jørgensen, T, Møller, L, Jespersen, J, Dankner, R, Chetrit, A, Lubin, F, Rosengren, A, Wilhelmsen, L, Lappas, G, Eriksson, H, Björkelund, C, Lissner, L, Bengtsson, C, Cremer, P, Nagel, D, Tilvis, R, Strandberg, Te, Kiyohara, Y, Arima, H, Doi, Y, Ninomiya, T, Rodriguez, B, Dekker, J, Nijpels, G, Stehouwer, Cd, Rimm, E, Pai, Jk, Sato, S, Iso, H, Kitamura, A, Noda, H, Salonen, Jt, Nyyssönen, K, Tuomainen, Tp, Laukkanen, Ja, Deeg, Dj, Bremmer, Ma, Meade, Tw, Cooper, Ja, Hedblad, B, Berglund, G, Engström, G, Verschuren, Wm, Blokstra, A, Shea, S, Döring, A, Koenig, W, Meisinger, C, Bueno de Mesquita, Hb, Kuller, Lh, Grandits, G, Selmer, R, Tverdal, A, Nystad, W, Gillum, Rf, Mussolino, M, Hankinson, S, Manson, Je, Knottenbelt, C, Bauer, Ka, Davidson, K, Kirkland, S, Shaffer, J, Korin, Mr, Naito, Y, Holme, I, Nakagawa, H, Miura, K, Ducimetiere, P, Jouven, X, Luc, G, Crespo, Cj, Garcia Palmieri, Mr, Amouyel, P, Arveiler, D, Evans, A, Ferrieres, J, Schulte, H, Assmann, G, Packard, Cj, Sattar, N, Westendorp, Rg, Buckley, Bm, Cantin, B, Lamarche, B, Després, Jp, Dagenais, Gr, Barrett Connor, E, Wingard, Dl, Bettencourt, Rr, Gudnason, V, Aspelund, T, Sigurdsson, G, Thorsson, B, Trevisan, M, Witteman, J, Kardys, I, Breteler, Mm, Hofman, A, Tunstall Pedoe, H, Tavendale, R, Howard, Bv, Zhang, Y, Best, L, Umans, J, Ben Shlomo, Y, Davey Smith, G, Onat, A, Njølstad, I, Mathiesen, Eb, Løchen, Ml, Wilsgaard, T, Ingelsson, E, Basu, S, Cederholm, T, Byberg, L, Gaziano, Jm, Stampfer, M, Ridker, Pm, Ulmer, H, Diem, G, Concin, H, Tosetto, A, Rodeghiero, F, Wassertheil Smoller, S, Marmot, Im, Clarke, R, Fletcher, A, Brunner, E, Shipley, M, Buring, J, Shepherd, J, Cobbe, S, Ford, I, Robertson, M, He, Y, Ibañez, Am, Feskens, Ej, Walker, M, Watson, S, Erqou, S, Lewington, S, Pennells, L, Perry, Pl, Ray, Kk, Sarwar, N, Alexander, M, Thompson, A, White, Ir, Wood, Am, and Danesh, J.

Subjects
Lung Diseases, Male, Databases, Factual, Plasma-fibrinogen, Blood Pressure, Coronary Disease, 030204 cardiovascular system & hematology, Associations, Body Mass Index, Low-density-lipoprotein, Leukocyte Count, 0302 clinical medicine, Risk Factors, Neoplasms, 030212 general & internal medicine, Stroke, Framingham Risk Score, biology, Smoking, 11 Medical And Health Sciences, General Medicine, Articles, Middle Aged, 3. Good health, C-Reactive Protein, Cholesterol, Regression Analysis, low-density lipoprotein cardiovascular-disease nonvascular mortality regression dilution plasma-fibrinogen mendelian randomization independent predictor prospective cohorts vascular-disease inflammation, Female, Risk assessment, medicine.medical_specialty, Alcohol Drinking, Regression dilution, Motor Activity, Risk Assessment, 03 medical and health sciences, Sex Factors, Cardiovascular-disease, General & Internal Medicine, Internal medicine, Diabetes Mellitus, medicine, Humans, Women, Risk factor, Serum Albumin, Triglycerides, Inflammation, Markers, Independent predictor, Interleukin-6, business.industry, Vascular disease, C-reactive protein, Fibrinogen, medicine.disease, Surgery, Relative risk, biology.protein, Nonvascular mortality, business, Biomarkers
Abstract

Udgivelsesdato: 2010-Jan-9 BACKGROUND: Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances. METHODS: We meta-analysed individual records of 160 309 people without a history of vascular disease (ie, 1.31 million person-years at risk, 27 769 fatal or non-fatal disease outcomes) from 54 long-term prospective studies. Within-study regression analyses were adjusted for within-person variation in risk factor levels. RESULTS: Log(e) CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischaemic vascular disease and non-vascular mortality. Risk ratios (RRs) for coronary heart disease per 1-SD higher log(e) CRP concentration (three-fold higher) were 1.63 (95% CI 1.51-1.76) when initially adjusted for age and sex only, and 1.37 (1.27-1.48) when adjusted further for conventional risk factors; 1.44 (1.32-1.57) and 1.27 (1.15-1.40) for ischaemic stroke; 1.71 (1.53-1.91) and 1.55 (1.37-1.76) for vascular mortality; and 1.55 (1.41-1.69) and 1.54 (1.40-1.68) for non-vascular mortality. RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1.23 (1.07-1.42) for coronary heart disease; 1.32 (1.18-1.49) for ischaemic stroke; 1.34 (1.18-1.52) for vascular mortality; and 1.34 (1.20-1.50) for non-vascular mortality. INTERPRETATION: CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. The relevance of CRP to such a range of disorders is unclear. Associations with ischaemic vascular disease depend considerably on conventional risk factors and other markers of inflammation. FUNDING: British Heart Foundation, UK Medical Research Council, BUPA Foundation, and GlaxoSmithKline.

Published
2010
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16. Emerging Risk Factors Collaboration. Statistical methods for the time-to-event analysis of individual participant data from multiple epidemiological studies

Author

hompson S, Kaptoge S, White I, Wood A, Thompson SG, White IR, Wood AM, Perry PL, Danesh J, Tipping RW, Ford CE, Simpson LM, Walldius G, Jungner I, Chambless LE, Panagiotakos DB, Pitsavos C, Chrysohoou C, Stefanadis C, Knuiman M, Goldbourt U, Benderly M, Tanne D, Whincup PH, Wannamethee SG, Morris RW, Willeit J, Kiechl S, Santer P, Mayr A, Lawlor DA, Yarnell JW, Gallacher J, Casiglia E, Tikhonoff V, Nietert PJ, Sutherland SE, Bachman DL, Keil JE, Cushman M, Tracy RP, Tybjærg Hansen A, Nordestgaard BG, Benn M, Frikke Schmidt R, Giampaoli S, Palmieri L, Vanuzzo D, Gómez de la Cámara A, Gómez Gerique JA, Simons L, McCallum J, Friedlander Y, Fowkes FG, Lee AJ, Taylor J, Guralnik JM, Wallace R, Guralnik J, Blazer DG, Khaw KT, Brenner H, Raum E, Müller H, Rothenbacher D, Jansson JH, Wennberg P, Nissinen A, Donfrancesco C, Salomaa V, Harald K, Jousilahti P, Vartiainen E, Woodward M, D'Agostino RB, Vasan RS, Pencina MJ, Bladbjerg EM, Jørgensen T, Møller L, Jespersen J, Dankner R, Chetrit A, Lubin F, Rosengren A, Lappas G, Björkelund C, Lissner L, Bengtsson C, Cremer P, Nagel D, Tilvis RS, Strandberg TE, Kiyohara Y, Arima H, Doi Y, Ninomiya T, Rodriguez B, Dekker JM, Nijpels G, Stehouwer CD, Rimm E, Pai JK, Sato S, Iso H, Kitamura A, Noda H, Salonen JT, Tuomainen TP, Deeg DJ, Poppelaars JL, Meade TW, Cooper JA, Hedblad B, Berglund G, Engstrom G, Verschuren WM, Blokstra A, Shea S, Döring A, Koenig W, Meisinger C, Mraz W, Bas Bueno de Mesquita H, Kuller LH, Grandits G, Selmer R, Tverdal A, Nystad W, Gillum R, Mussolino M, Hankinson S, Manson JE, Knottenbelt C, Bauer KA, Naito Y, Holme I, Nakagawa H, Miura K, Ducimetiere P, Jouven X, Crespo CJ, Garcia MR, Amouyel P, Arveiler D, Evans A, Ferrieres J, Schulte H, Assmann G, Shepherd J, Packard CJ, Sattar N, Ford I, Cantin B, Després JP, Dagenais GR, Barrett Connor E, Wingard DL, Bettencourt R, Gudnason V, Aspelund T, Sigurdsson G, Thorsson B, Trevisan M, Witteman J, Kardys I, Breteler M, Hofman A, Tunstall Pedoe H, Tavendale R, Lowe GD, Ben Shlomo Y, Davey Smith G, Howard BV, Zhang Y, Umans J, Onat A, Wilsgaard T, Ingelsson E, Lind L, Giedraitis V, Lannfelt L, Gaziano JM, Ridker P, Ulmer H, Diem G, Concin H, Tosetto A, Rodeghiero F, Wassertheil Smoller S, Marmot M, Clarke R, Collins R, Brunner E, Shipley M, Buring J, Cobbe SM, Robertson M, He Y, Marín Ibañez A, Feskens EJ, Kromhout D, Di Angelantonio E, Erqou S, Lewington S, Orfei L, Pennells L, Ray KK, Sarwar N, Alexander M, Thompson A, Walker M, Watson S, Wensley F, Perry P, Danesh J., PANICO, SALVATORE, Hompson, S, Kaptoge, S, White, I, Wood, A, Thompson, Sg, White, Ir, Wood, Am, Perry, Pl, Danesh, J, Tipping, Rw, Ford, Ce, Simpson, Lm, Walldius, G, Jungner, I, Chambless, Le, Panagiotakos, Db, Pitsavos, C, Chrysohoou, C, Stefanadis, C, Knuiman, M, Goldbourt, U, Benderly, M, Tanne, D, Whincup, Ph, Wannamethee, Sg, Morris, Rw, Willeit, J, Kiechl, S, Santer, P, Mayr, A, Lawlor, Da, Yarnell, Jw, Gallacher, J, Casiglia, E, Tikhonoff, V, Nietert, Pj, Sutherland, Se, Bachman, Dl, Keil, Je, Cushman, M, Tracy, Rp, Tybjærg Hansen, A, Nordestgaard, Bg, Benn, M, Frikke Schmidt, R, Giampaoli, S, Palmieri, L, Panico, Salvatore, Vanuzzo, D, Gómez de la Cámara, A, Gómez Gerique, Ja, Simons, L, Mccallum, J, Friedlander, Y, Fowkes, Fg, Lee, Aj, Taylor, J, Guralnik, Jm, Wallace, R, Guralnik, J, Blazer, Dg, Khaw, Kt, Brenner, H, Raum, E, Müller, H, Rothenbacher, D, Jansson, Jh, Wennberg, P, Nissinen, A, Donfrancesco, C, Salomaa, V, Harald, K, Jousilahti, P, Vartiainen, E, Woodward, M, D'Agostino, Rb, Vasan, R, Pencina, Mj, Bladbjerg, Em, Jørgensen, T, Møller, L, Jespersen, J, Dankner, R, Chetrit, A, Lubin, F, Rosengren, A, Lappas, G, Björkelund, C, Lissner, L, Bengtsson, C, Cremer, P, Nagel, D, Tilvis, R, Strandberg, Te, Kiyohara, Y, Arima, H, Doi, Y, Ninomiya, T, Rodriguez, B, Dekker, Jm, Nijpels, G, Stehouwer, Cd, Rimm, E, Pai, Jk, Sato, S, Iso, H, Kitamura, A, Noda, H, Salonen, Jt, Tuomainen, Tp, Deeg, Dj, Poppelaars, Jl, Meade, Tw, Cooper, Ja, Hedblad, B, Berglund, G, Engstrom, G, Verschuren, Wm, Blokstra, A, Shea, S, Döring, A, Koenig, W, Meisinger, C, Mraz, W, Bas Bueno de Mesquita, H, Kuller, Lh, Grandits, G, Selmer, R, Tverdal, A, Nystad, W, Gillum, R, Mussolino, M, Hankinson, S, Manson, Je, Knottenbelt, C, Bauer, Ka, Naito, Y, Holme, I, Nakagawa, H, Miura, K, Ducimetiere, P, Jouven, X, Crespo, Cj, Garcia, Mr, Amouyel, P, Arveiler, D, Evans, A, Ferrieres, J, Schulte, H, Assmann, G, Shepherd, J, Packard, Cj, Sattar, N, Ford, I, Cantin, B, Després, Jp, Dagenais, Gr, Barrett Connor, E, Wingard, Dl, Bettencourt, R, Gudnason, V, Aspelund, T, Sigurdsson, G, Thorsson, B, Trevisan, M, Witteman, J, Kardys, I, Breteler, M, Hofman, A, Tunstall Pedoe, H, Tavendale, R, Lowe, Gd, Ben Shlomo, Y, Davey Smith, G, Howard, Bv, Zhang, Y, Umans, J, Onat, A, Wilsgaard, T, Ingelsson, E, Lind, L, Giedraitis, V, Lannfelt, L, Gaziano, Jm, Ridker, P, Ulmer, H, Diem, G, Concin, H, Tosetto, A, Rodeghiero, F, Wassertheil Smoller, S, Marmot, M, Clarke, R, Collins, R, Brunner, E, Shipley, M, Buring, J, Cobbe, Sm, Robertson, M, He, Y, Marín Ibañez, A, Feskens, Ej, Kromhout, D, Di Angelantonio, E, Erqou, S, Lewington, S, Orfei, L, Pennells, L, Ray, Kk, Sarwar, N, Alexander, M, Thompson, A, Walker, M, Watson, S, Wensley, F, Perry, P, and Danesh, J.

Published
2010

17. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality

Author

Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Tipping RW, Ford CE, Simpson LM, Walldius G, Jungner I, Folsom AR, Chambless L, Panagiotakos D, Pitsavos C, Chrysohoou C, Stefanadis C, Goldbourt U, Benderly M, Tanne D, Whincup P, Wannamethee SG, Morris RW, Kiechl S, Willeit J, Santer P, Mayr A, Wald N, Ebrahim S, Lawlor D, Yarnell J, Gallacher J, Casiglia E, Tikhonoff V, Nietert PJ, Sutherland SE, Bachman DL, Cushman M, Psaty BM, Tracy R, Tybjaerg Hansen A, Nordestgaard BG, Frikke Schmidt R, Kamstrup PR, Giampaoli S, Palmieri L, Vanuzzo D, Pilotto L, Gómez de la Cámara A, Gómez Gerique JA, Simons L, McCallum J, Friedlander Y, Fowkes FG, Lee A, Smith FB, Taylor J, Guralnik JM, Phillips CL, Wallace RB, Blazer DG, Brenner H, Raum E, Müller H, Rothenbacher D, Jansson JH, Wennberg P, Nissinen A, Donfrancesco C, Salomaa V, Harald K, Jousilahti P, Vartiainen E, Woodward M, D'Agostino RB, Wolf PA, Vasan RS, Pencina MJ, Bladbjerg EM, Jørgensen T, Møller L, Jespersen J, Dankner R, Chetrit A, Lubin F, Rosengren A, Wilhelmsen L, Lappas G, Eriksson H, Björkelund C, Lissner L, Bengtsson C, Cremer P, Nagel D, Tilvis RS, Strandberg TE, Rodriguez B, Dekker J, Nijpels G, Stehouwer CD, Rimm E, Pai JK, Sato S, Iso H, Kitamura A, Noda H, Salonen JT, Nyyssönen K, Tuomainen TP, Deeg DJ, Poppelaars JL, Hedblad B, Berglund G, Engström G, Verschuren WM, Blokstra A, Döring A, Koenig W, Meisinger C, Mraz W, Bueno de Mesquita HB, Kuller LH, Grandits G, Selmer R, Tverdal A, Nystad W, Gillum RF, Mussolino M, Hankinson S, Manson JE, Cooper JA, Bauer KA, Naito Y, Holme I, Nakagawa H, Miura K, Ducimetiere P, Jouven X, Luc G, Crespo CJ, Garcia Palmieri MR, Amouyel P, Arveiler D, Evans A, Ferrieres J, Schulte H, Assmann G, Shepherd J, Packard CJ, Sattar N, Ford I, Cantin B, Lamarche B, Després JP, Dagenais GR, Barrett Connor E, Daniels LB, Laughlin GA, Gudnason V, Aspelund T, Sigurdsson G, Thorsson B, Trevisan M, Witteman J, Kardys I, Breteler MM, Hofman A, Tunstall Pedoe H, Tavendale R, Lowe G, Ben Shlomo Y, Davey Smith G, Howard BV, Zhang Y, Best L, Umans J, Onat A, Njølstad I, Mathiesen EB, Løchen ML, Wilsgaard T, Ingelsson E, Sundström J, Lind L, Lannfelt L, Gaziano JM, Stampfer M, Ridker PM, Ulmer H, Diem G, Concin H, Tosetto A, Rodeghiero F, Marmot M, Clarke R, Fletcher A, Brunner E, Shipley M, Buring J, Cobbe S, Robertson M, He Y, Marin Ibanñez A, Feskens E, Kromhout D, Walker M, Watson S, Lewington S, Orfei L, Pennells L, Ray KK, Sarwar N, Alexander M, Wensley F, Wood AM, Danesh J., PANICO, SALVATORE, Developmental Genetics, EMGO+ - Lifestyle, Overweight and Diabetes, Emerging Risk Factors, Collaboration, Erqou, S, Kaptoge, S, Perry, Pl, Di Angelantonio, E, Thompson, A, White, Ir, Marcovina, Sm, Collins, R, Thompson, Sg, Tipping, Rw, Ford, Ce, Simpson, Lm, Walldius, G, Jungner, I, Folsom, Ar, Chambless, L, Panagiotakos, D, Pitsavos, C, Chrysohoou, C, Stefanadis, C, Goldbourt, U, Benderly, M, Tanne, D, Whincup, P, Wannamethee, Sg, Morris, Rw, Kiechl, S, Willeit, J, Santer, P, Mayr, A, Wald, N, Ebrahim, S, Lawlor, D, Yarnell, J, Gallacher, J, Casiglia, E, Tikhonoff, V, Nietert, Pj, Sutherland, Se, Bachman, Dl, Cushman, M, Psaty, Bm, Tracy, R, Tybjaerg Hansen, A, Nordestgaard, Bg, Frikke Schmidt, R, Kamstrup, Pr, Giampaoli, S, Palmieri, L, Panico, Salvatore, Vanuzzo, D, Pilotto, L, Gómez de la Cámara, A, Gómez Gerique, Ja, Simons, L, Mccallum, J, Friedlander, Y, Fowkes, Fg, Lee, A, Smith, Fb, Taylor, J, Guralnik, Jm, Phillips, Cl, Wallace, Rb, Blazer, Dg, Brenner, H, Raum, E, Müller, H, Rothenbacher, D, Jansson, Jh, Wennberg, P, Nissinen, A, Donfrancesco, C, Salomaa, V, Harald, K, Jousilahti, P, Vartiainen, E, Woodward, M, D'Agostino, Rb, Wolf, Pa, Vasan, R, Pencina, Mj, Bladbjerg, Em, Jørgensen, T, Møller, L, Jespersen, J, Dankner, R, Chetrit, A, Lubin, F, Rosengren, A, Wilhelmsen, L, Lappas, G, Eriksson, H, Björkelund, C, Lissner, L, Bengtsson, C, Cremer, P, Nagel, D, Tilvis, R, Strandberg, Te, Rodriguez, B, Dekker, J, Nijpels, G, Stehouwer, Cd, Rimm, E, Pai, Jk, Sato, S, Iso, H, Kitamura, A, Noda, H, Salonen, Jt, Nyyssönen, K, Tuomainen, Tp, Deeg, Dj, Poppelaars, Jl, Hedblad, B, Berglund, G, Engström, G, Verschuren, Wm, Blokstra, A, Döring, A, Koenig, W, Meisinger, C, Mraz, W, Bueno de Mesquita, Hb, Kuller, Lh, Grandits, G, Selmer, R, Tverdal, A, Nystad, W, Gillum, Rf, Mussolino, M, Hankinson, S, Manson, Je, Cooper, Ja, Bauer, Ka, Naito, Y, Holme, I, Nakagawa, H, Miura, K, Ducimetiere, P, Jouven, X, Luc, G, Crespo, Cj, Garcia Palmieri, Mr, Amouyel, P, Arveiler, D, Evans, A, Ferrieres, J, Schulte, H, Assmann, G, Shepherd, J, Packard, Cj, Sattar, N, Ford, I, Cantin, B, Lamarche, B, Després, Jp, Dagenais, Gr, Barrett Connor, E, Daniels, Lb, Laughlin, Ga, Gudnason, V, Aspelund, T, Sigurdsson, G, Thorsson, B, Trevisan, M, Witteman, J, Kardys, I, Breteler, Mm, Hofman, A, Tunstall Pedoe, H, Tavendale, R, Lowe, G, Ben Shlomo, Y, Davey Smith, G, Howard, Bv, Zhang, Y, Best, L, Umans, J, Onat, A, Njølstad, I, Mathiesen, Eb, Løchen, Ml, Wilsgaard, T, Ingelsson, E, Sundström, J, Lind, L, Lannfelt, L, Gaziano, Jm, Stampfer, M, Ridker, Pm, Ulmer, H, Diem, G, Concin, H, Tosetto, A, Rodeghiero, F, Marmot, M, Clarke, R, Fletcher, A, Brunner, E, Shipley, M, Buring, J, Cobbe, S, Robertson, M, He, Y, Marin Ibanñez, A, Feskens, E, Kromhout, D, Walker, M, Watson, S, Lewington, S, Orfei, L, Pennells, L, Ray, Kk, Sarwar, N, Alexander, M, Wensley, F, Wood, Am, and Danesh, J.

Subjects
medicine.medical_specialty, Context (language use), Coronary Disease, Article, Risk Factors, General & Internal Medicine, Internal medicine, Cause of Death, medicine, Humans, Myocardial infarction, Prospective cohort study, Stroke, biology, business.industry, 11 Medical And Health Sciences, General Medicine, Lipoprotein(a), medicine.disease, Surgery, Relative risk, Nested case-control study, biology.protein, business, Cohort study
Abstract

Udgivelsesdato: 2009-Jul-22 CONTEXT: Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes. STUDY SELECTION: Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators. DATA EXTRACTION: Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline. DATA SYNTHESIS: Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer. CONCLUSION: Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.

Published
2009
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18. The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases

Author

Danesh, J, Erqou, S, Walker, M, Thompson, Sg, Tipping, R, Ford, C, Pressel, S, Walldius, G, Jungner, I, Folsom, Ar, Chambless, Le, Knuiman, M, Whincup, Ph, Wannamethee, Sg, Morris, Rw, Willeit, J, Kiechl, S, Santer, P, Mayr, A, Wald, N, Ebrahim, S, Lawlor, Da, Yarnell, Jw, Gallacher, J, Casiglia, Edoardo, Tikhonoff, Valerie, Nietert, Pj, Sutherland, Se, Bachman, Dl, Keil, Je, Cushman, M, Psaty, Bm, Tracy, Rp, Tybjaerg Hansen, A, Nordestgaard, Bg, Frikke Schmidt, R, Giampaoli, S, Palmieri, L, Panico, S, Vanuzzo, D, Pilotto, L, Simons, L, Mccallum, J, Friedlander, Y, Fowkes, Fg, Lee, Aj, Smith, Fb, Taylor, J, Guralnik, J, Phillips, C, Wallace, R, Blazer, D, Khaw, Kt, Jansson, Jh, Donfrancesco, C, Salomaa, V, Harald, K, Jousilahti, P, Vartiainen, E, Woodward, M, D'Agostino, Rb, Wolf, Pa, Vasan, Rs, Pencina, Mj, Bladbjerg, Em, Jorgensen, T, Moller, L, Jespersen, J, Dankner, R, Chetrit, A, Lubin, F, Rosengren, A, Wilhelmsen, L, Lappas, G, Eriksson, H, Bjorkelund, C, Cremer, P, Nagel, D, Tilvis, R, Strandberg, T, Rodriguez, B, Bouter, Lm, Heine, Rj, Dekker, Jm, Nijpels, G, Stehouwer, Cd, Rimm, E, Pai, J, Sato, S, Iso, H, Kitamura, A, Noda, H, Goldbourt, U, Salonen, Jt, Nyyssönen, K, Tuomainen, Tp, Deeg, D, Poppelaars, Jl, Meade, T, Cooper, J, Hedblad, B, Berglund, G, Engstrom, G, Döring, A, Koenig, W, Meisinger, C, Mraz, W, Kuller, L, Selmer, R, Tverdal, A, Nystad, W, Gillum, R, Mussolino, M, Hankinson, S, Manson, J, De Stavola, B, Knottenbelt, C, Cooper, Ja, Bauer, Ka, Rosenberg, Rd, Naito, Y, Holme, I, Nakagawa, H, Miura, H, Ducimetiere, P, Jouven, X, Crespo, C, Garcia Palmieri, M, Amouyel, P, Arveiler, D, Evans, A, Ferrieres, J, Schulte, H, Assmann, G, Shepherd, J, Packard, C, Sattar, N, Cantin, B, Lamarche, B, Després, Jp, Dagenais, Gr, Barrett Connor, E, Wingard, D, Bettencourt, R, Gudnason, V, Aspelund, T, Sigurdsson, G, Thorsson, B, Trevisan, M, Witteman, J, Kardys, I, Breteler, M, Hofman, A, Tunstall Pedoe, H, Tavendale, R, Lowe, Gd, Ben Shlomo, Y, Howard, Bv, Zhang, Y, Best, L, Umans, J, Onat, A, Meade, Tw, Njolstad, I, Mathiesen, E, Lochen, Ml, Wilsgaard, T, Gaziano, Jm, Stampfer, M, Ridker, P, Ulmer, H, Diem, G, Concin, H, Rodeghiero, F, Tosetto, A, Brunner, E, Shipley, M, Buring, J, Cobbe, Sm, Ford, I, Robertson, M, He, Y, Ibanez, Am, Feskens, Ej, Kromhout, D, Collins, R, Di Angelantonio, E, Kaptoge, S, Lewington, S, Orfei, L, Pennells, L, Perry, P, Ray, K, Sarwar, N, Scherman, M, Thompson, A, Watson, S, Wensley, F, White, Ir, Wood, Am, Emerging Risk Factors Collaboration, Interne Geneeskunde, RS: NUTRIM School of Nutrition and Translational Research in Metabolism, RS: CARIM School for Cardiovascular Diseases, Movement Behavior, Executive board Vrije Universiteit, Clinical Child and Family Studies, Sociology and Social Gerontology, Earth and Climate, Environmental Policy Analysis, Developmental Genetics, Danesh, J, Erqou, S, Walker, M, Thompson, Sg, Tipping, R, Ford, C, Pressel, S, Walldius, G, Jungner, I, Folsom, Ar, Chambless, Le, Knuiman, M, Whincup, Ph, Wannamethee, Sg, Morris, Rw, Willeit, J, Kiechl, S, Santer, P, Mayr, A, Wald, N, Ebrahim, S, Lawlor, Da, Yarnell, Jw, Gallacher, J, Casiglia, E, Tikhonoff, V, Nietert, Pj, Sutherland, Se, Bachman, Dl, Keil, Je, Cushman, M, Psaty, Bm, Tracy, Rp, Tybjaerg Hansen, A, Nordestgaard, Bg, Frikke Schmidt, R, Giampaoli, S, Palmieri, L, Panico, Salvatore, Vanuzzo, D, Pilotto, L, Simons, L, Mccallum, J, Friedlander, Y, Fowkes, Fg, Lee, Aj, Smith, Fb, Taylor, J, Guralnik, J, Phillips, C, Wallace, R, Blazer, D, Khaw, Kt, Jansson, Jh, Donfrancesco, C, Salomaa, V, Harald, K, Jousilahti, P, Vartiainen, E, Woodward, M, D'Agostino, Rb, Wolf, Pa, Vasan, R, Pencina, Mj, Bladbjerg, Em, Jorgensen, T, Moller, L, Jespersen, J, Dankner, R, Chetrit, A, Lubin, F, Rosengren, A, Wilhelmsen, L, Lappas, G, Eriksson, H, Bjorkelund, C, Cremer, P, Nagel, D, Tilvis, R, Strandberg, T, Rodriguez, B, Bouter, Lm, Heine, Rj, Dekker, Jm, Nijpels, G, Stehouwer, Cd, Rimm, E, Pai, J, Sato, S, Iso, H, Kitamura, A, Noda, H, Goldbourt, U, Salonen, Jt, Nyyssönen, K, Tuomainen, Tp, Deeg, D, Poppelaars, Jl, Meade, T, Cooper, J, Hedblad, B, Berglund, G, Engstrom, G, Döring, A, Koenig, W, Meisinger, C, Mraz, W, Kuller, L, Selmer, R, Tverdal, A, Nystad, W, Gillum, R, Mussolino, M, Hankinson, S, Manson, J, De Stavola, B, Knottenbelt, C, Cooper, Ja, Bauer, Ka, Rosenberg, Rd, Naito, Y, Holme, I, Nakagawa, H, Miura, H, Ducimetiere, P, Jouven, X, Crespo, C, Garcia Palmieri, M, Amouyel, P, Arveiler, D, Evans, A, Ferrieres, J, Schulte, H, Assmann, G, Shepherd, J, Packard, C, Sattar, N, Cantin, B, Lamarche, B, Després, Jp, Dagenais, Gr, Barrett Connor, E, Wingard, D, Bettencourt, R, Gudnason, V, Aspelund, T, Sigurdsson, G, Thorsson, B, Trevisan, M, Witteman, J, Kardys, I, Breteler, M, Hofman, A, Tunstall Pedoe, H, Tavendale, R, Lowe, Gd, Ben Shlomo, Y, Howard, Bv, Zhang, Y, Best, L, Umans, J, Onat, A, Meade, Tw, Njolstad, I, Mathiesen, E, Lochen, Ml, Wilsgaard, T, Gaziano, Jm, Stampfer, M, Ridker, P, Ulmer, H, Diem, G, Concin, H, Rodeghiero, F, Tosetto, A, Brunner, E, Shipley, M, Buring, J, Cobbe, Sm, Ford, I, Robertson, M, He, Y, Ibanez, Am, Feskens, Ej, Kromhout, D, Collins, R, Di Angelantonio, E, Kaptoge, S, Lewington, S, Orfei, L, Pennells, L, Perry, P, Ray, K, Sarwar, N, Scherman, M, Thompson, A, Watson, S, Wensley, F, White, Ir, and Wood, A. M.

Subjects
Databases, Factual, Nutrition and Disease, Epidemiology, Inflammatory markers, middle-aged men, Disease, Leukocyte Count, c-reactive protein, Risk Factors, Voeding en Ziekte, adult-treatment-panel, Prospective Studies, Myocardial infarction, Prospective cohort study, education.field_of_study, biology, plasma-fibrinogen, Asia, Eastern, Confounding, density-lipoprotein cholesterol, Cardiovascular disease, Lipids, myocardial-infarction, Coronary heart disease, Cardiovascular Diseases, Meta-analysis, Lipoproteins, HDL, high blood cholesterol, medicine.medical_specialty, low-dose aspirin, Population, 10-year follow-up, SDG 3 - Good Health and Well-being, Albumins, medicine, Humans, education, Triglycerides, VLAG, Inflammation, Estimation, business.industry, C-reactive protein, medicine.disease, Surgery, Emergency medicine, biology.protein, business, coronary-heart-disease, Biomarkers
Abstract

Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age-and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily,with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.

Published
2007
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20. Statistical methods for the time-to-event analysis of individual participant data from multiple epidemiological studies

Author

Thompson, S. Kaptoge, S. White, I. Wood, A. Perry, P. Danesh, J. The Emerging Risk Factors Collaboration Thompson, S.G. Kaptoge, S. White, I.R. Wood, A.M. Perry, P.L. Tipping, R.W. Ford, C.E. Simpson, L.M. Walldius, G. Jungner, I. Chambless, L.E. Panagiotakos, D.B. Pitsavos, C. Chrysohoou, C. Stefanadis, C. Knuiman, M. Goldbourt, U. Benderly, M. Tanne, D. Whincup, P.H. Wannamethee, S.G. Morris, R.W. Willeit, J. Kiechl, S. Santer, P. Mayr, A. Lawlor, D.A. Yarnell, J.W.G. Gallacher, J. Casiglia, E. Tikhonoff, V. Nietert, P.J. Sutherland, S.E. Bachman, D.L. Keil, J.E. Cushman, M. Tracy, R.P. Tybjærg-Hansen, A. Nordestgaard, B.G. Benn, M. Frikke- Schmidt, R. Giampaoli, S. Palmieri, L. Panico, S. Vanuzzo, D. Gómez de la Cámara, A. Gómez- Gerique, J.A. Simons, L. McCallum, J. Friedlander, Y. Fowkes, F.G.R. Lee, A.J. Taylor, J. Guralnik, J.M. Wallace, R. Guralnik, J. Blazer, D.G. Guralnik, J.M. Guralnik, J.M. Khaw, K.-T. Brenner, H. Raum, E. Müller, H. Rothenbacher, D. Jansson, J.H. Wennberg, P. Nissinen, A. Donfrancesco, C. Salomaa, V. Harald, K. Jousilahti, P. Vartiainen, E. Woodward, M. D'Agostino, R.B. Vasan, R.S. Pencina, M.J. Bladbjerg, E.M. Jørgensen, T. Jespersen, J. Møller, L. Dankner, R. Chetrit, A. Lubin, F. Rosengren, A. Lappas, G. Björkelund, C. Lissner, L. Bengtsson, C. Cremer, P. Nagel, D. Tilvis, R.S. Strandberg, T.E. Kiyohara, Y. Arima, H. Doi, Y. Ninomiya, T. Rodriguez, B. Dekker, J.M. Nijpels, G. Stehouwer, C.D.A. Rimm, E. Pai, J.K. Sato, S. Kitamura, A. Iso, H. Goldbourt, U. Noda, H. Harald, K. Jousilahti, P. Vartiainen, E. Salonen, J.T. Tuomainen, T.-P. Deeg, D.J.H. Poppelaars, J.L. Meade, T.W. Cooper, J.A. Hedblad, B. Berglund, G. Engstrom, G. Verschuren, W.M.M. Blokstra, A. Cushman, M. Shea, S. Döring, A. Koenig, W. Meisinger, C. Mraz, W. Bas Bueno-de-Mesquita, H. Kuller, L.H. Grandits, G. Selmer, R. Tverdal, A. Nystad, W. Gillum, R. Mussolino, M. Rimm, E. Manson, J.E. Pai, J.K. Meade, T.W. Cooper, J.A. Cooper, J.A. Knottenbelt, C. Bauer, K.A. Naito, Y. Holme, I. Hankinson, S. Tverdal, A. Nystad, W. Nakagawa, H. Miura, K. Ducimetiere, P. Jouven, X. Crespo, C.J. Garcia Palmieri, M.R. Amouyel, P. Arveiler, D. Evans, A. Ferrieres, J. Schulte, H. Assmann, G. Shepherd, J. Packard, C.J. Sattar, N. Ford, I. Cantin, B. Després, J.-P. Dagenais, G.R. Barrett-Connor, E. Wingard, D.L. Bettencourt, R. Gudnason, V. Aspelund, T. Sigurdsson, G. Thorsson, B. Trevisan, M. Witteman, J. Kardys, I. Breteler, M. Hofman, A. Tunstall-Pedoe, H. Tavendale, R. Lowe, G.D.O. Ben-Shlomo, Y. Howard, B.V. Zhang, Y. Umans, J. Onat, A. Davey-Smith, G. Wilsgaard, T. Ingelsson, E. Lind, L. Giedraitis, V. Lannfelt, L. Gaziano, J.M. Ridker, P. Gaziano, J.M. Ridker, P. Ulmer, H. Diem, G. Concin, H. Tosetto, A. Rodeghiero, F. Wassertheil-Smoller, S. Manson, J.E. Marmot, M. Clarke, R. Collins, R. Brunner, E. Shipley, M. Ridker, P. Buring, J. Shepherd, J. Cobbe, S.M. Robertson, M. He, Y. Marín Ibañez, A. Feskens, E.J.M. Kromhout, D. Collins, R. Di Angelantonio, E. Erqou, S. Kaptoge, S. Lewington, S. Orfei, L. Pennells, L. Perry, P.L. Ray, K.K. Sarwar, N. Alexander, M. Thompson, A. Thompson, S.G. Walker, M. Watson, S. Wensley, F. White, I.R. Wood, A.M.

Abstract

Background Meta-analysis of individual participant time-to-event data from multiple prospective epidemiological studies enables detailed investigation of exposure-risk relationships, but involves a number of analytical challenges. Methods This article describes statistical approaches adopted in the Emerging Risk Factors Collaboration, in which primary data from more than 1 million participants in more than 100 prospective studies have been collated to enable detailed analyses of various risk markers in relation to incident cardiovascular disease outcomes. Results Analyses have been principally based on Cox proportional hazards regression models stratified by sex, undertaken in each study separately. Estimates of exposure-risk relationships, initially unadjusted and then adjusted for several confounders, have been combined over studies using meta-analysis. Methods for assessing the shape of exposure-risk associations and the proportional hazards assumption have been developed. Estimates of interactions have also been combined using meta-analysis, keeping separate within-and between-study information. Regression dilution bias caused by measurement error and within-person variation in exposures and confounders has been addressed through the analysis of repeat measurements to estimate corrected regression coefficients. These methods are exemplified by analysis of plasma fibrinogen and risk of coronary heart disease, and Stata code is made available. Conclusion Increasing numbers of meta-analyses of individual participant data from observational data are being conducted to enhance the statistical power and detail of epidemiological studies. The statistical methods developed here can be used to address the needs of such analyses. © The Author 2010; all rights reserved.

Published
2010

21. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality

Author

Tipping, R.W. Ford, C.E. Simpson, L.M. Walldius, G. Jungner, I. Folsom, A.R. Chambless, L. Panagiotakos, D. Pitsavos, C. Chrysohoou, C. Stefanadis, C. Goldbourt, U. Benderly, M. Tanne, D. Whincup, P. Wannamethee, S.G. Morris, R.W. Kiechl, S. Willeit, J. Santer, P. Mayr, A. Wald, N. Ebrahim, S. Lawlor, D. Yarnell, J. Gallacher, J. Casiglia, E. Tikhonoff, V. Nietert, P.J. Sutherland, S.E. Bachman, D.L. Cushman, M. Psaty, B.M. Tracy, R. Tybjærg-Hansen, A. Nordestgaard, B.G. Frikke-Schmidt, R. Kamstrup, P.R. Giampaoli, S. Palmieri, L. Panico, S. Vanuzzo, D. Pilotto, L. De La Cámara, A.G. Gómez Gerique, J.A. Simons, L. McCallum, J. Friedlander, Y. Fowkes, F.G.R. Lee, A. Smith, F.B. Taylor, J. Guralnik, J.M. Phillips, C.L. Wallace, R.B. Blazer, D.G. Brenner, H. Raum, E. Müller, H. Rothenbacher, D. Jansson, J.-H. Wennberg, P. Nissinen, A. Donfrancesco, C. Salomaa, V. Harald, K. Jousilahti, P. Vartiainen, E. Woodward, M. D’Agostino, R.B. Wolf, P.A. Vasan, R.S. Pencina, M.J. Bladbjerg, E.-M. Jørgensen, T. Møller, L. Jespersen, J. Dankner, R. Chetrit, A. Lubin, F. Rosengren, A. Wilhelmsen, L. Lappas, G. Eriksson, H. Björkelund, C. Lissner, L. Bengtsson, C. Cremer, P. Nagel, D. Tilvis, R.S. Strandberg, T.E. Rodriguez, B. Dekker, J. Nijpels, G. Stehouwer, C.D.A. Rimm, E. Pai, J.K. Sato, S. Iso, H. Kitamura, A. Noda, H. Salonen, J.T. Nyyssönen, K. Tuomainen, T.-P. Deeg, D.J.H. Poppelaars, J.L. Hedblad, B. Berglund, G. Engström, G. Verschuren, W.M.M. Blokstra, A. Döring, A. Koenig, W. Meisinger, C. Mraz, W. Bueno-De-Mesquita, H.B. Kuller, L.H. Grandits, G. Selmer, R. Tverdal, A. Nystad, W. Gillum, R.F. Mussolino, M. Hankinson, S. Manson, J.E. Cooper, J.A. Bauer, K.A. Naito, Y. Holme, I. Nakagawa, H. Miura, K. Ducimetiere, P. Jouven, X. Luc, G. Crespo, C.J. Garcia Palmieri, M.R. Amouyel, P. Arveiler, D. Evans, A. Ferrieres, J. Schulte, H. Assmann, G. Shepherd, J. Packard, C.J. Sattar, N. Ford, I. Cantin, B. Lamarche, B. Després, J.-P. Dagenais, G.R. Barrett-Connor, E. Daniels, L.B. Laughlin, G.A. Gudnason, V. Aspelund, T. Sigurdsson, G. Thorsson, B. Trevisan, M. Witteman, J. Kardys, I. Breteler, M.M.B. Hofman, A. Tunstall-Pedoe, H. Tavendale, R. Lowe, G. Ben-Shlomo, Y. Davey-Smith, G. Howard, B.V. Zhang, Y. Best, L. Umans, J. Onat, A. Njølstad, I. Mathiesen, E.B. Løchen, M.-L. Wilsgaard, T. Ingelsson, E. Sundström, J. Lind, L. Lannfelt, L. Gaziano, J.M. Stampfer, M. Ridker, P.M. Ulmer, H. Diem, G. Concin, H. Tosetto, A. Rodeghiero, F. Marmot, M. Clarke, R. Collins, R. Fletcher, A. Brunner, E. Shipley, M. Buring, J. Cobbe, S. Robertson, M. He, Y. Ibañez, A.M. Feskens, E. Kromhout, D. Walker, M. Watson, S. Di Angelantonio, E. Erqou, S. Kaptoge, S. Lewington, S. Orfei, L. Pennells, L. Perry, P.L. Ray, K.K. Sarwar, N. Alexander, M. Thompson, A. Thompson, S.G. Wensley, F. White, I.R. Wood, A.M. Danesh, J.

Abstract

Context Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein–like particle, may be associated with risk of coronary heart disease (CHD) and stroke. Objective To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes. Study Selection Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators. Data Extraction Individual records were provided for each of 126 634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22 076 firstever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline. Data Synthesis Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 personyears and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer. Conclusion Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes. ©2009 American Medical Association. All rights reserved.

Published
2009

27. Metabolic syndrome and rare gynecological cancers in the Metabolic syndrome and Cancer project (Me-Can)

Author

Nagel, G, Concin, H, Bjørge, T, Rapp, K, Manjer, J, Hallmans, Göran, Diem, G, Häggström, Christel, Engeland, A, Almquist, M, Jonsson, Håkan, Selmer, R, Stocks, Tanja, Tretli, S, Ulmer, H, Stattin, Pär, Lukanova, A, Nagel, G, Concin, H, Bjørge, T, Rapp, K, Manjer, J, Hallmans, Göran, Diem, G, Häggström, Christel, Engeland, A, Almquist, M, Jonsson, Håkan, Selmer, R, Stocks, Tanja, Tretli, S, Ulmer, H, Stattin, Pär, and Lukanova, A

Abstract

BACKGROUND: Risk factors for rare gynecological cancers are largely unknown. Initial research has indicated that the metabolic syndrome (MetS) or individual components could play a role. Materials and methods: The Metabolic syndrome and Cancer project cohort includes 288 834 women. During an average follow-up of 11 years, 82 vulvar, 26 vaginal and 43 other rare gynecological cancers were identified. Hazard ratios (HRs) were estimated fitting Cox proportional hazards regression models for tertiles and standardized z-scores [with a mean of 0 and a standard deviation (SD) of 1] of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and MetS. Risk estimates were corrected for random error in the measurement of metabolic factors. RESULTS: The MetS was associated with increased risk of vulvar [HR 1.78, 95% confidence interval (CI) 1.30-2.41) and vaginal cancer (HR 1.87, 95% CI 1.07-3.25). Among separate MetS components, 1 SD increase in BMI was associated with overall risk (HR 1.43, 95% CI 1.23-1.66), vulvar (HR 1.36, 95% CI 1.11-1.69) and vaginal cancer (HR 1.79, 95% CI 1.30-2.46). Blood glucose and triglyceride concentrations were associated with increased risk of vulvar cancer (HR 1.98, 95% CI 1.10-3.58 and HR 2.09, 95% CI 1.39-3.15, respectively). CONCLUSION: The results from this first prospective study on rare gynecological cancers suggest that the MetS and its individual components may play a role in the development of these tumors.

Published
2011
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37. Signification clinique de la répartition en sous-classes des IgG anti-acide désoxyribonucléique natif au cours du lupus érythémateux disséminé

Author

Dueymes, M., primary, Pennec, Y.L., additional, Barrier, J., additional, Besancenot, J.F., additional, Cledes, J., additional, Conri, Cl., additional, Diem, G., additional, Drosos, A., additional, Dueymes, J.M., additional, Galanaud, P., additional, Grobois, B., additional, Guillevin, L., additional, Hatron, P.Y., additional, Isenberg, D., additional, Jorgensen, Ch., additional, Jouquan, J., additional, Le Goff, P., additional, Longy-Boursier, M., additional, Massot, Ch., additional, Meyer, O., additional, Mottier, D., additional, Moutsopoulos, H., additional, Philippe, P., additional, Piette, J.Ch., additional, Sany, J., additional, Series, Cl., additional, Shoenfeld, Y., additional, and Youinou, P., additional

Published
1991
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38. Serum triglyceride concentrations and cancer risk in a large cohort study in Austria.

Author

Ulmer, H., Borena, W., Rapp, K., Klenk, J., Strasak, A., Diem, G., Concin, H., and Nagel, G.

Subjects
CANCER in women, TRIGLYCERIDES, MALE reproductive organs, HODGKIN'S disease, BLOOD lipids, RELATIVE medical risk, TUMORS, LONGITUDINAL method, FEMALE reproductive organ tumors, PROSTATE tumors
Abstract

Background: Blood lipid levels as part of the metabolic syndrome are thought to be linked to cancer risk. Few epidemiological studies have addressed the association between serum triglyceride (STG) concentrations and cancer risk.Methods: Serum triglyceride concentrations were collected in a health investigation (1988-2003). The analyses included 156 153 subjects (71 693 men and 84 460 women), with 5079 incident cancers in men and 4738 cancers in women, and an average of 10.6 years of follow-up. All malignancies were ascertained from the population cancer registry. Multivariate Cox proportional hazard models stratified by age and sex were used to determine adjusted cancer risk estimates and 95% confidence interval (95% CI).Results: In men and women combined, higher STG concentrations were associated with increased risk of lung (4th vs 1st quartile: HR, 1.94; 95% CI, 1.47-2.54), rectal (HR, 1.56; 95% CI, 1.00-2.44), and thyroid cancer (HR, 1.96; 95% CI, 1.00-3.84). Serum triglyceride concentrations were inversely associated with non-Hodgkin's lymphoma. In men, STG concentrations were inversely associated with prostate cancer and positively with renal cancer. In women, STG concentrations were positively associated with gynaecological cancers. Stratification by BMI revealed a higher risk of gynaecological cancers in overweight than in normal weight women. No other associations were found.Conclusions: Our findings support the hypothesis that STG concentrations are involved in the pathogenesis of lung, rectal, thyroid, prostate, and gynaecological cancers. [ABSTRACT FROM AUTHOR]

Published
2009
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39. Secular trends in cardiovascular risk factors: an age-period cohort analysis of 698,954 health examinations in 181,350 Austrian men and women.

Author

Ulmer H, Kelleher CC, Fitz-Simon N, Diem G, and Concin H

Abstract

OBJECTIVES: It is well established that morbidity and mortality patterns in cardiovascular diseases vary strongly over time, yet the determinants of such trends remain poorly understood. To assess the potential contribution of secular or cross-generation patterns, we evaluated birth cohort-related trends across the 20th century of risk factors in a large database of Austrian men and women. SUBJECTS AND SETTING: Trends in risk factors were investigated for 181,350 adults aged 20-79 years born between 1905 and 1975 undergoing 698,954 health examinations between 1985 and 2005 as participants of the Vorarlberg Health Monitoring and Promotion Programme. RESULTS: There was clear evidence of cohort-related shifts in all risk factors. Total serum cholesterol and triglyceride declined markedly, particularly in the youngest cohorts, as did systolic and diastolic blood pressure in both men and women. By contrast, fasting glucose showed a strong rising tendency in both sexes and at all ages, most markedly in young males. Average glucose levels were between 4 and 15 mg dL(-1) higher in individuals at the same age born 20 years later. In males, body weight expressed in kg m(-2) (body mass index) was increasing as well; however, in women, patterns were most marked at the 90th percentile. CONCLUSION: These findings provide strong evidence of population wide secular shifts and suggest that in addition to period influences, most probably through treatment intervention and lifestyle change, determinants across the life-course are programming shifts from childhood onwards. [ABSTRACT FROM AUTHOR]

Published
2007
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42. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies

Author

Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M, Stehouwer CD, Lewington S, Pennells L, Thompson A, Sattar N, White IR, Ray KK, Danesh J. Tipping RW, Ford CE, Pressel SL, Folsom AR, Chambless LE, Wagenknecht LE, Panagiotakos DB, Pitsavos C, Chrysohoou C, Stefanadis C, Knuiman M, Whincup PH, Wannamethee SG, Morris RW, Kiechl S, Willeit J, Oberhollenzer F, Mayr A, Wald N, Ebrahim S, Yarnell JW, Gallacher J, Casiglia E, Tikhonoff V, Nietert PJ, Sutherland SE, Bachman DL, Keil JE, de Boer IH, Kizer JR, Mukamal KJ, Tybjaerg Hansen A, Nordestgaard BG, Benn M, Frikke Schmidt R, Palmieri L, Vanuzzo D, Pilotto L, de la Cámara AG, Rubio MA, Simons L, McCallum J, Friedlander Y, Fowkes FG, Lee AJ, Taylor J, Guralnik JM, Phillips CL, Wallace R, Blazer DG, Khaw KT, Brenner H, Raum E, Müller H, Rothenbacher D, Jansson JH, Wennberg P, Nissinen A, Donfrancesco C, Giampaoli S, Salomaa V, Harald K, Jousilahti P, Vartiainen E, Woodward M, D'Agostino RB, Vasan RS, Fox CS, Pencina MJ, Bladbjerg E, Jørgensen T, Møller L, Jespersen J, Dankner R, Chetrit A, Lubin F, Wilhelmsen L, Eriksson H, Svärdsudd K, Welin L, Rosengren A, Lappas G, Björkelund C, Lissner L, Bengtsson C, Cremer P, Nagel D, Strandberg TE, Tilvis RS, Miettinen TA, Kiyohara Y, Arima H, Doi Y, Ninomiya T, Rodriguez B, Dekker JM, Nijpels G, Rimm E, Pai JK, Sato S, Iso H, Kitamura A, Noda H, Goldbourt U, Nyyssönen K, Tuomainen TP, Salonen JT, Deeg D, Poppelaars JL, Meade TW, Cooper JA, Hedblad B, Berglund G, Engström G, Verschuren WM, Blokstra A, Cushman M, Psaty BM, Shea S, Döring A, Koenig W, Meisinger C, Mraz W, Bueno de Mesquita HB, Fletcher A, Kuller LH, Grandits G, Selmer R, Tverdal A, Nystad W, Gillum R, Mussolino M, Hankinson S, Manson JE, Bauer KA, Davidson KW, Kirkland S, Shaffer J, Korin MR, Holme I, Ducimetiere P, Jouven X, Bakker SJ, Gansevoort RT, Hillege HL, Crespo CJ, Garcia Palmieri MR, Amouyel P, Arveiler D, Evans A, Ferrières J, Schulte H, Assmann G, Westendorp RG, Buckley BM, Packard CJ, Cantin B, Lamarche B, Després JP, Dagenais GR, Barrett Connor E, Wingard DL, Bettencourt R, Gudnason V, Aspelund T, Sigurdsson G, Thorsson B, Trevisan M, Witteman J, Kardys I, Breteler M, Hofman A, Tunstall Pedoe H, Tavendale R, Lowe GD, Howard BV, Zhang Y, Best L, Umans J, Ben Shlomo Y, Davey Smith G, Onat A, Hergenç G, Can G, Njølstad I, Mathiesen EB, Løchen ML, Wilsgaard T, Zethelius B, Risérus U, Berne C, Gaziano JM, Ridker P, Ulmer H, Diem G, Concin H, Tosetto A, Rodeghiero F, Tinker L, Liu S, Marmot IM, Clarke R, Collins R, Brunner E, Shipley M, Buring J, Shepherd J, Cobbe SM, Ford I, Robertson M, Ibañez AM, Feskens EJ, Kromhout D, Walker M, Watson S, Alexander M, Erqou S, Haycock P, Perry PL, Thompson SG, Wood AM, Wormser D, Danesh J., PANICO, SALVATORE, Interne Geneeskunde, RS: NUTRIM - R1 - Metabolic Syndrome, RS: CARIM School for Cardiovascular Diseases, Emerging Risk Factors, Collaboration, Sarwar, N, Gao, P, Seshasai, Sr, Gobin, R, Kaptoge, S, Di Angelantonio, E, Ingelsson, E, Lawlor, Da, Selvin, E, Stampfer, M, Stehouwer, Cd, Lewington, S, Pennells, L, Thompson, A, Sattar, N, White, Ir, Ray, Kk, Danesh J., Tipping RW, Ford, Ce, Pressel, Sl, Folsom, Ar, Chambless, Le, Wagenknecht, Le, Panagiotakos, Db, Pitsavos, C, Chrysohoou, C, Stefanadis, C, Knuiman, M, Whincup, Ph, Wannamethee, Sg, Morris, Rw, Kiechl, S, Willeit, J, Oberhollenzer, F, Mayr, A, Wald, N, Ebrahim, S, Yarnell, Jw, Gallacher, J, Casiglia, E, Tikhonoff, V, Nietert, Pj, Sutherland, Se, Bachman, Dl, Keil, Je, de Boer, Ih, Kizer, Jr, Mukamal, Kj, Tybjaerg Hansen, A, Nordestgaard, Bg, Benn, M, Frikke Schmidt, R, Palmieri, L, Panico, Salvatore, Vanuzzo, D, Pilotto, L, de la Cámara, Ag, Rubio, Ma, Simons, L, Mccallum, J, Friedlander, Y, Fowkes, Fg, Lee, Aj, Taylor, J, Guralnik, Jm, Phillips, Cl, Wallace, R, Blazer, Dg, Khaw, Kt, Brenner, H, Raum, E, Müller, H, Rothenbacher, D, Jansson, Jh, Wennberg, P, Nissinen, A, Donfrancesco, C, Giampaoli, S, Salomaa, V, Harald, K, Jousilahti, P, Vartiainen, E, Woodward, M, D'Agostino, Rb, Vasan, R, Fox, C, Pencina, Mj, Bladbjerg, E, Jørgensen, T, Møller, L, Jespersen, J, Dankner, R, Chetrit, A, Lubin, F, Wilhelmsen, L, Eriksson, H, Svärdsudd, K, Welin, L, Rosengren, A, Lappas, G, Björkelund, C, Lissner, L, Bengtsson, C, Cremer, P, Nagel, D, Strandberg, Te, Tilvis, R, Miettinen, Ta, Kiyohara, Y, Arima, H, Doi, Y, Ninomiya, T, Rodriguez, B, Dekker, Jm, Nijpels, G, Rimm, E, Pai, Jk, Sato, S, Iso, H, Kitamura, A, Noda, H, Goldbourt, U, Nyyssönen, K, Tuomainen, Tp, Salonen, Jt, Deeg, D, Poppelaars, Jl, Meade, Tw, Cooper, Ja, Hedblad, B, Berglund, G, Engström, G, Verschuren, Wm, Blokstra, A, Cushman, M, Psaty, Bm, Shea, S, Döring, A, Koenig, W, Meisinger, C, Mraz, W, Bueno de Mesquita, Hb, Fletcher, A, Kuller, Lh, Grandits, G, Selmer, R, Tverdal, A, Nystad, W, Gillum, R, Mussolino, M, Hankinson, S, Manson, Je, Bauer, Ka, Davidson, Kw, Kirkland, S, Shaffer, J, Korin, Mr, Holme, I, Ducimetiere, P, Jouven, X, Bakker, Sj, Gansevoort, Rt, Hillege, Hl, Crespo, Cj, Garcia Palmieri, Mr, Amouyel, P, Arveiler, D, Evans, A, Ferrières, J, Schulte, H, Assmann, G, Westendorp, Rg, Buckley, Bm, Packard, Cj, Cantin, B, Lamarche, B, Després, Jp, Dagenais, Gr, Barrett Connor, E, Wingard, Dl, Bettencourt, R, Gudnason, V, Aspelund, T, Sigurdsson, G, Thorsson, B, Trevisan, M, Witteman, J, Kardys, I, Breteler, M, Hofman, A, Tunstall Pedoe, H, Tavendale, R, Lowe, Gd, Howard, Bv, Zhang, Y, Best, L, Umans, J, Ben Shlomo, Y, Davey Smith, G, Onat, A, Hergenç, G, Can, G, Njølstad, I, Mathiesen, Eb, Løchen, Ml, Wilsgaard, T, Zethelius, B, Risérus, U, Berne, C, Gaziano, Jm, Ridker, P, Ulmer, H, Diem, G, Concin, H, Tosetto, A, Rodeghiero, F, Tinker, L, Liu, S, Marmot, Im, Clarke, R, Collins, R, Brunner, E, Shipley, M, Buring, J, Shepherd, J, Cobbe, Sm, Ford, I, Robertson, M, Ibañez, Am, Feskens, Ej, Kromhout, D, Walker, M, Watson, S, Alexander, M, Erqou, S, Haycock, P, Perry, Pl, Thompson, Sg, Wood, Am, Wormser, D, Danesh, J., and University of Groningen

Subjects
Adult, Blood Glucose, Male, medicine.medical_specialty, PATHOPHYSIOLOGY, 030209 endocrinology & metabolism, Coronary Disease, Disease, 030204 cardiovascular system & hematology, THERAPY, Diabetes Complications, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Diabetes mellitus, Internal medicine, General & Internal Medicine, medicine, Diabetes Mellitus, Humans, CORONARY-HEART-DISEASE, Prospective cohort study, Stroke, Aged, Glucose Metabolism Disorders, business.industry, Vascular disease, MORTALITY, Absolute risk reduction, ASIA-PACIFIC REGION, WOMEN, General Medicine, Fasting, 11 Medical And Health Sciences, Articles, Middle Aged, medicine.disease, Impaired fasting glucose, 3. Good health, Endocrinology, Blood pressure, ATHEROSCLEROSIS, Cardiovascular Diseases, CARDIOVASCULAR-DISEASES, Female, coronary-heart-disease asia-pacific region cardiovascular-diseases task-force pathophysiology atherosclerosis mortality therapy women, business, TASK-FORCE
Abstract

Summary Background Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. Methods We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. Findings Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8·49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2·00 (95% CI 1·83–2·19) for coronary heart disease; 2·27 (1·95–2·65) for ischaemic stroke; 1·56 (1·19–2·05) for haemorrhagic stroke; 1·84 (1·59–2·13) for unclassified stroke; and 1·73 (1·51–1·98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40–59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10–12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3·90 mmol/L and 5·59 mmol/L. Compared with fasting blood glucose concentrations of 3·90–5·59 mmol/L, HRs for coronary heart disease were: 1·07 (0·97–1·18) for lower than 3·90 mmol/L; 1·11 (1·04–1·18) for 5·60–6·09 mmol/L; and 1·17 (1·08–1·26) for 6·10–6·99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. Interpretation Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. Funding British Heart Foundation, UK Medical Research Council, and Pfizer.

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43. Recent trends and sociodemographic distribution of cardiovascular risk factors: results from two population surveys in the Austrian WHO CINDI demonstration area

Author

Hanno Ulmer, Diem, G., Bischof, Hp, Ruttmann, E., and Concin, H.

Subjects
Adult, Male, Health Knowledge, Attitudes, Practice, Health Behavior, Health Promotion, Middle Aged, World Health Organization, Health Surveys, Cross-Sectional Studies, Cardiovascular Diseases, Risk Factors, Austria, Humans, Female, Life Style
Abstract

The major risk factors for cardiovascular diseases are well established; however, only a few studies report on recent trends in risk factor profiles. This study analyses the sociodemographic distribution of risk factors and gives an account of their changes from 1991 to 1999.Two cross-sectional population surveys as part of the CINDI (Countrywide Integrated Noncommunicable Diseases Intervention) program of the World Health Organization were performed in 1991 and 1999 in the province of Vorarlberg (Austria). The surveys included a standardized interview and a medical examination. 1863 persons aged 25 to 64 years in 1991 and 1550 persons in 1999 participated in the interview section of the surveys. From these, 1446 in 1991 and 841 persons in 1999 underwent medical examination. Prevalence of overweight and obesity, mild and severe hypertension, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, regular smoking and lack of physical activity were estimated. Framingham risk functions were calculated to compare overall risk for coronary heart disease.In women, prevalence of overweight including obesity increased from 34% in 1991 to 41% in 1999. Almost 50% of the male population were estimated to be overweight or obese in 1991 and 1999. Hypertension showed a favorable trend and decreased substantially in both genders. Hypercholesterolemia decreased only in men, from 27% to 21%. In 1999, women aged 55-64 showed a prevalence of over 50% in highly elevated cholesterol. Hypertriglyceridemia decreased in men from 21% to 18%, in women it remained almost unchanged. Total prevalence of smoking did not change from 1991 to 1999. 34% of the men and 24% of the women reported to smoke more than one cigarette daily. In women under 45 years of age, regular smoking increased slightly and reached a prevalence of over 30%. Less educated people and people of non-national origin had significantly higher risk factor levels. The risk functions did not reveal a significant difference in 10 year risk for coronary heart disease between the two surveys.Decreasing levels in hypertension and in male hypercholesterolemia showed favorable developments in risk factor prevalence. Preventive measures should concentrate on reducing overweight in older people and smoking in young women as well as on intensifying the care for less educated people and people of non-national origin.

44. P80 natural essence spray and lozenges provide respiratory protection against Influenza A, B, and SARS-CoV-2.

Author

Zaderer V, Diem G, Posch W, Jakschitz T, Bonn GK, Bellmann-Weiler R, Huber LA, and Wilflingseder D

Subjects
Humans, Influenza A Virus, H3N2 Subtype, SARS-CoV-2, Inflammation, Influenza, Human prevention & control, COVID-19
Abstract

Seasonally circulating viruses, such as Influenza, as well as newly emerging viruses and variants thereof, and waning immunity urge the need for safe, easy-to-use and inexpensive drugs to protect from these challenges. To prevent transmission of these viruses and subsequent excessive inflammatory reactions on mucous membranes, we tested the efficacy of the natural essence P80 as spray and in form of lozenges against respiratory infections caused by SARS-CoV-2 variants of concern (VoCs), influenza A (H3N2) and influenza B (Victoria). P80 natural essence, a Dimocarpus longan extract, shielded highly differentiated human airway epithelia from SARS-CoV-2 wildtype and Omicron variant as well as Influenza A and B infection and dampened inflammation by down-modulating pro-inflammatory cytokine and anaphylatoxin secretion. A single application of P80 natural essence spray maintained tissue integrity long-term. This also significantly reduced the release of infectious viral particles and the secretion of IP10, MCP1, RANTES and C3a, all of which mediate the migration of immune cells to the sites of infection. Even P80 lozenges dissolved in distilled water or non-neutralizing saliva efficiently prevented SARS-CoV-2 and Influenza-induced tissue destruction. Consequently, our in vitro data suggest that P80 natural essence can act as antiviral prophylactic, both in form of nasal or oral spray and in form of lozenges, independent of circulating respiratory challenges., (© 2024. The Author(s).)

Published
2024
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45. Salivary antibodies induced by BA.4/BA.5-convalescence or bivalent booster Immunoglobulin vaccination protect against novel SARS-COV-2 variants of concern.

Author

Diem G, Dichtl S, Zaderer V, Lass-Flörl C, Reindl M, Lupoli G, Dächert C, Muenchhoff M, Graf A, Blum H, Keppler OT, Wilflingseder D, and Posch W

Abstract

Currently, SARS-CoV-2 Omicron BA.5 subvariants BF.7 and BQ.1.1 are rapidly emerging worldwide. To evaluate the SARS-CoV-2-neutralizing capacity of sera and saliva from triple vaccinated individuals, either boosted with an adapted bivalent COVID-19 vaccine or recovered from BA.4/BA.5 infection, we analyzed the sensitivity of replication-competent SARS-CoV-2 Omicron subvariants BA.4/5, BQ.1.1 and BF.7 to neutralization. Analysis of SARS-CoV-2-specific IgGs and IgAs showed increased serum IgG titers in the vaccinated group, while the serum and salivary IgA levels were comparable. Similar and efficient serum neutralization against the ancestral strain of SARS-CoV-2 and Omicron BA.4/BA.5 was detected in both cohorts, but critically reduced for BQ.1.1 and BF.7. In contrast, salivary neutralization against BA.4/BA.5 was increased in the convalescent compared to the vaccinated group, while salivary neutralizing capacity against BQ.1.1 and BF.7 was comparable in these groups. Further, personalized protective effects studied in a human 3D respiratory model revealed the importance of salivary protection against different Omicron subvariants. IMPORTANCE In BA.4/BA.5-convalescent versus vaccinated groups, salivary neutralization capacity increased against SARS-CoV-2 Omicron BA.4/BA.5. In contrast, it neutralized novel Omicron subvariants BQ.1.1 and BF.7 similarly. Salivary protection against various Omicron subvariants was even more evident when tested in a personalized approach using highly differentiated respiratory human 3D models.

Published
2023
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46. Immunity of Heterologously and Homologously Boosted or Convalescent Individuals Against Omicron BA.1, BA.2, and BA.4/5 Variants.

Author

Jäger M, Diem G, Sahanic S, Fux V, Griesmacher A, Lass-Flörl C, Wilflingseder D, Tancevski I, and Posch W

Subjects
Humans, Leukocytes, Mononuclear, SARS-CoV-2 genetics, Antibodies, Viral, RNA, Messenger, Antibodies, Neutralizing, BNT162 Vaccine, COVID-19
Abstract

Background: The emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants BA.1, BA.2, and BA.4/5 demonstrate higher transmission and infection rates than previous variants of concern. To evaluate effectiveness of heterologous and homologous booster vaccination, we directly compared cellular and humoral immune responses as well as neutralizing capacity against replication-competent SARS-CoV-2 wild type, Delta, and Omicron variants BA.1, BA.2, and BA.4/5., Methods: Peripheral blood mononuclear cells and serum samples from 137 participants were investigated, in 3 major groups. Individuals in the first group were vaccinated twice with ChAdOx1 and boosted with a messenger RNA (mRNA) vaccine (BNT162b2 or mRNA-1273); the second group included triple mRNA--vaccinated participants, and the third group, twice-vaccinated and convalescent individuals., Results: Vaccination and convalescence resulted in the highest SARS-CoV-2-specific antibody levels, stronger T-cell responses, and best neutralization against wild type, Delta Omicron BA.2, and BA.4/5, while a combination of ChAdOx1 and BNT162b2 vaccination elevated neutralizing capacity against Omicron BA.1. In addition, heterologous booster regimens, compared with homologous regimens, showed higher efficacy against Omicron BA.2 as well as BA.4/5., Conclusions: We showed that twice-vaccinated and convalescent individuals demonstrated the strongest immunity against Omicron BA.2 and BA.4/5 variant, followed by those receiving heterologous and homologous booster vaccine regimens., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Published
2023
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47. Intravesical BCG in bladder cancer induces innate immune responses against SARS-CoV-2.

Author

Pichler R, Diem G, Hackl H, Koutník J, Mertens LS, D Andrea D, Pradere B, Soria F, Mari A, Laukhtina E, Krajewski W, Teoh JY, Del Guidice F, Moschini M, Thurnher M, and Posch W

Subjects
Humans, SARS-CoV-2, BCG Vaccine, Leukocytes, Mononuclear, Immunity, Innate, Cytokines metabolism, COVID-19, Urinary Bladder Neoplasms
Abstract

BCG is the most efficient adjuvant therapy for high-risk, non-muscle-invasive bladder cancer (NMIBC). Both innate and adaptive immune responses have been implicated in BCG-mediated effects. BCG vaccination can boost innate immune responses via trained immunity (TI), resulting in an increased resistance to respiratory viral infections. Here we evaluated for the first time whether intravesical application of BCG triggers increased immunity against SARS-CoV-2 in patients with high-risk NMIBC. Serum and peripheral blood mononuclear cells (PBMCs) from heparinized whole blood samples of 11 unvaccinated SARS-CoV-2-naïve high-risk NMIBC patients were collected at baseline and during BCG treatment in a pre-COVID-19 era. To examine B-cell or T cell-dependent adaptive immunity against SARS-CoV-2, sera were tested for the presence of SARS-CoV-2 neutralizing antibodies. Using a SARS-CoV-2 peptide pool, virus-specific T cells were quantified via IFNγ ELISpot assays. To analyze innate immune responses, mRNA and protein expression levels of pro- and anti-inflammatory cytokines were measured after a 24-hour stimulation of PBMCs with either BCG or SARS-CoV-2 wildtype. ATAC- sequencing was performed to identify a potential epigenetic reprogramming in immune cells. We neither identified SARS-CoV-2 neutralizing antibodies nor SARS-CoV-2- reactive T cells, indicating that intravesical BCG did not induce adaptive immunity against SARS-CoV-2. However, a significant increase in mRNA as well as protein expression of IL-1β, IL-6 and TNFα, which are key cytokines of trained immunity, could be observed after at least four intravesical BCG instillations. Genomic regions in the proximity of TI genes ( TLR2 , IGF1R , AKT1, MTOR, MAPK14, HSP90AA1 ) were more accessible during BCG compared to baseline. Although intravesical BCG did not induce adaptive immune responses, repetitive intravesical instillations of BCG induced circulating innate immune cells that produce TI cytokines also in response to SARS-CoV-2., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pichler, Diem, Hackl, Koutník, Mertens, D`Andrea, Pradere, Soria, Mari, Laukhtina, Krajewski, Teoh, Del Guidice, Moschini, Thurnher and Posch.)

Published
2023
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48. Vaccination and Omicron BA.1/BA.2 Convalescence Enhance Systemic but Not Mucosal Immunity against BA.4/5.

Author

Diem G, Jäger M, Dichtl S, Bauer A, Lass-Flörl C, Reindl M, Wilflingseder D, and Posch W

Subjects
Humans, BNT162 Vaccine, COVID-19 Vaccines, 2019-nCoV Vaccine mRNA-1273, Cohort Studies, Convalescence, Vaccination, Antibodies, Neutralizing, Antibodies, Viral, Breakthrough Infections, Immunoglobulin A, SARS-CoV-2, COVID-19 prevention & control
Abstract

Rising breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.4/5 led to the performance of various studies investigating systemic immunity and neutralizing antibodies in sera, but mucosal immunity remains understudied. In this cohort study, the humoral immune responses, including immunoglobulin levels and the presence of virus-neutralizing antibodies, of 92 vaccinated and/or BA.1/BA.2 convalescent individuals were investigated. Cohorts received two doses of ChAdOx1, BNT162b2, or mRNA-1273 and subsequent booster vaccination with either BNT162b2 or mRNA-1273, following BA.1/BA.2 infection. In addition, vaccinated and nonconvalescent or unvaccinated and BA.1 convalescent individuals were studied. Serum and saliva samples were used to determine SARS-CoV-2 spike-specific IgG and IgA titers and neutralizing activity against replication-competent SARS-CoV-2 wild-type virus and the Omicron BA.4/5 variant. Vaccinated/convalescent cohorts demonstrated strongest neutralization against BA.4/5, with 50% neutralization titer (NT 50 ) values reaching 174.2; however, neutralization was reduced up to 11-fold, compared to wild-type virus. Both BA.1 convalescent and vaccinated nonconvalescent cohorts displayed the weakest neutralization against BA.4/5, with NT 50 values being reduced to 4.6, accompanied by lower numbers of positive neutralizers. Additionally, salivary neutralization against wild-type virus was strongest in vaccinated and BA.2 convalescent subjects, but this elevated neutralization efficiency was lost when challenged with BA.4/5. Our data support the contention that current coronavirus disease 2019 (COVID-19) vaccines efficiently induce humoral immunity. However, antiviral effectiveness in serum and saliva is greatly reduced against novel variants of concern. These results suggest an adjustment of current vaccine strategies to an adapted or alternative vaccine delivery, such as mucosal booster vaccinations, which might establish enhanced or even sterilizing immunity against novel SARS-CoV-2 variants. IMPORTANCE Rising incidences of breakthrough infections caused by SARS-CoV-2 Omicron BA.4/5 have been observed. Although various studies were conducted investigating neutralizing antibodies in sera, mucosal immunity was barely evaluated. Here, we investigated mucosal immunity, since the presence of neutralizing antibodies at mucosal entry sites plays a fundamental role in disease limitation. We found strong induction of serum IgG/IgA, salivary IgA, and neutralization against SARS-CoV-2 wild-type virus in vaccinated/convalescent subjects but detected 10-fold reduced (albeit positive) serum neutralization against BA.4/5. Interestingly, vaccinated and BA.2 convalescent patients demonstrated the greatest serum neutralization against BA.4/5, but this advantageous neutralizing effect was not observed in the saliva. Our data support the contention that current COVID-19 vaccines are very efficient against severe/critical disease progression. Moreover, these results suggest an adjustment of the current vaccine strategy to adapted and alternative vaccine delivery, such as mucosal booster vaccinations, to establish robust sterilizing immunity against novel SARS-CoV-2 variants., Competing Interests: The authors declare no conflict of interest.

Published
2023
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49. Antiviral drugs block replication of highly immune-evasive Omicron subvariants ex vivo, but fail to reduce tissue inflammation.

Author

Dichtl S, Diem G, Jäger M, Zaderer V, Lupoli G, Dächert C, Muenchhoff M, Graf A, Blum H, Keppler OT, Lass-Flörl C, Weiss G, Wilflingseder D, and Posch W

Subjects
Humans, SARS-CoV-2, Antibodies, Monoclonal, Antibodies, Neutralizing pharmacology, Antiviral Agents pharmacology, Antibodies, Viral, COVID-19
Abstract

The identification of the SARS-CoV-2 Omicron variants BA.4/BA.5, BF.7 and BQ.1.1 immediately raised concerns regarding the efficacy of currently used monoclonal antibody therapies. Here we examined the activity of monoclonal antibody therapies and antiviral drugs against clinical specimens for SARS-CoV-2 Omicron BA.4/BA.5, BF.7 and BQ.1.1 employing an immunofluorescence neutralization assay. Further we explored treatment of BA.4/BA.5 infections with efficient antiviral drugs and monoclonal antibodies in a 3D model of primary human bronchial epithelial cells. We found that the antiviral drugs Molnupiravir, Nirmatrelvir and Remdesivir efficiently inhibit BA.4/BA.5, BF.7 and BQ.1.1 replication. In contrast, only the monoclonal antibody Cilgavimab exerted an inhibitory effect, while Tixagevimab, Regdanvimab and Sotrovimab lost their efficacy against BA.4/BA.5. We found that only the prophylactic treatment with Cilgavimab impacted on tissue inflammation by reducing intracellular complement component 3 (C3) activation following BA.4/BA.5 infection in primary human airway epithelial grown in air-liquid-interphase, which was not the case when using antiviral drugs or Cilgavimab after establishment of infection. Of note, all tested monoclonal antibodies had no neutralizing activity during infection by BF.7 and BQ.1.1 variants. Our results suggest that despite a marked reduction of viral replication, potent antiviral drugs fail to reduce tissue levels of inflammatory compounds such as C3, which can still result in tissue destruction., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2023
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