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  • 1. Adams, D.
    et al.
    Gonzalez-Duarte, A.
    O'Riordan, W. D.
    Yang, C. -C
    Ueda, M.
    Kristen, A. V.
    Tournev, I.
    Schmidt, H. H.
    Coelho, T.
    Berk, J. L.
    Lin, K. -P
    Vita, G.
    Attarian, S.
    Plante-Bordeneuve, V.
    Mezei, M. M.
    Campistol, J. M.
    Buades, J.
    Brannagan, T. H. , I I I
    Kim, B. J.
    Oh, J.
    Parman, Y.
    Sekijima, Y.
    Hawkins, P. N.
    Solomon, S. D.
    Polydefkis, M.
    Dyck, P. J.
    Gandhi, P. J.
    Goyal, S.
    Chen, J.
    Strahs, A. L.
    Nochur, S. V.
    Sweetser, M. T.
    Garg, P. P.
    Vaishnaw, A. K.
    Gollob, J. A.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis2018In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, no 1, p. 11-21Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin.

    METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters] x albumin level in grams per liter; lower values indicated worse nutritional status).

    RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (+/- SD) mNIS+7 at baseline was 80.9 +/- 41.5 in the patisiran group and 74.6 +/- 37.0 in the placebo group; the least-squares mean (+/- SE) change from baseline was -6.0 +/- 1.7 versus 28.0 +/- 2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (+/- SD) baseline Norfolk QOL-DN score was 59.6 +/- 28.2 in the patisiran group and 55.5 +/- 24.3 in the placebo group; the least-squares mean (+/- SE) change from baseline was -6.7 +/- 1.8 versus 14.4 +/- 2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08 +/- 0.02 m per second with patisiran versus -0.24 +/- 0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7 +/- 9.6 versus -119.4 +/- 14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups.

    CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis.

  • 2. Afshin, Ashkan
    et al.
    Forouzanfar, Mohammad H.
    Reitsma, Marissa B.
    Sur, Patrick
    Estep, Kara
    Lee, Alex
    Marczak, Laurie
    Mokdad, Ali H.
    Moradi-Lakeh, Maziar
    Naghavi, Mohsen
    Salama, Joseph S.
    Vos, Theo
    Abate, Kalkidan H.
    Abbafati, Cristiana
    Ahmed, Muktar B.
    Al-Aly, Ziyad
    Alkerwi, Ala'a
    Al-Raddadi, Rajaa
    Amare, Azmeraw T.
    Amberbir, Alemayehu
    Amegah, Adeladza K.
    Amini, Erfan
    Amrock, Stephen M.
    Anjana, Ranjit M.
    Arnlov, Johan
    Asayesh, Hamid
    Banerjee, Amitava
    Barac, Aleksandra
    Baye, Estifanos
    Bennett, Derrick A.
    Beyene, Addisu S.
    Biadgilign, Sibhatu
    Biryukov, Stan
    Bjertness, Espen
    Boneya, Dube J.
    Campos-Nonato, Ismael
    Carrero, Juan J.
    Cecilio, Pedro
    Cercy, Kelly
    Ciobanu, Liliana G.
    Cornaby, Leslie
    Damtew, Solomon A.
    Dandona, Lalit
    Dandona, Rakhi
    Dharmaratne, Samath D.
    Duncan, Bruce B.
    Eshrati, Babak
    Esteghamati, Alireza
    Feigin, Valery L.
    Fernandes, Joao C.
    Furst, Thomas
    Gebrehiwot, Tsegaye T.
    Gold, Audra
    Gona, Philimon N.
    Goto, Atsushi
    Habtewold, Tesfa D.
    Hadush, Kokeb T.
    Hafezi-Nejad, Nima
    Hay, Simon I.
    Horino, Masako
    Islami, Farhad
    Kamal, Ritul
    Kasaeian, Amir
    Katikireddi, Srinivasa V.
    Kengne, Andre P.
    Kesavachandran, Chandrasekharan N.
    Khader, Yousef S.
    Khang, Young-Ho
    Khubchandani, Jagdish
    Kim, Daniel
    Kim, Yun J.
    Kinfu, Yohannes
    Kosen, Soewarta
    Ku, Tiffany
    Defo, Barthelemy Kuate
    Kumar, G. Anil
    Larson, Heidi J.
    Leinsalu, Mall
    Liang, Xiaofeng
    Lim, Stephen S.
    Liu, Patrick
    Lopez, Alan D.
    Lozano, Rafael
    Majeed, Azeem
    Malekzadeh, Reza
    Malta, Deborah C.
    Mazidi, Mohsen
    McAlinden, Colm
    McGarvey, Stephen T.
    Mengistu, Desalegn T.
    Mensah, George A.
    Mensink, Gert B. M.
    Mezgebe, Haftay B.
    Mirrakhimov, Erkin M.
    Mueller, Ulrich O.
    Noubiap, Jean J.
    Obermeyer, Carla M.
    Ogbo, Felix A.
    Owolabi, Mayowa O.
    Patton, George C.
    Pourmalek, Farshad
    Qorbani, Mostafa
    Rafay, Anwar
    Rai, Rajesh K.
    Ranabhat, Chhabi L.
    Reinig, Nikolas
    Safiri, Saeid
    Salomon, Joshua A.
    Sanabria, Juan R.
    Santos, Itamar S.
    Sartorius, Benn
    Sawhney, Monika
    Schmidhuber, Josef
    Schutte, Aletta E.
    Schmidt, Maria I.
    Sepanlou, Sadaf G.
    Shamsizadeh, Moretza
    Sheikhbahaei, Sara
    Shin, Min-Jeong
    Shiri, Rahman
    Shiue, Ivy
    Roba, Hirbo S.
    Silva, Diego A. S.
    Silverberg, Jonathan I.
    Singh, Jasvinder A.
    Stranges, Saverio
    Swaminathan, Soumya
    Tabares-Seisdedos, Rafael
    Tadese, Fentaw
    Tedla, Bemnet A.
    Tegegne, Balewgizie S.
    Terkawi, Abdullah S.
    Thakur, J. S.
    Tonelli, Marcello
    Topor-Madry, Roman
    Tyrovolas, Stefanos
    Ukwaja, Kingsley N.
    Uthman, Olalekan A.
    Vaezghasemi, Masoud
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Vasankari, Tommi
    Vlassov, Vasiliy V.
    Vollset, Stein E.
    Weiderpass, Elisabete
    Werdecker, Andrea
    Wesana, Joshua
    Westerman, Ronny
    Yano, Yuichiro
    Yonemoto, Naohiro
    Yonga, Gerald
    Zaidi, Zoubida
    Zenebe, Zerihun M.
    Zipkin, Ben
    Murray, Christopher J. L.
    Health Effects of Overweight and Obesity in 195 Countries over 25 Years2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 1, p. 13-27Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Although the rising pandemic of obesity has received major attention in many countries, the effects of this attention on trends and the disease burden of obesity remain uncertain. METHODS We analyzed data from 68.5 million persons to assess the trends in the prevalence of overweight and obesity among children and adults between 1980 and 2015. Using the Global Burden of Disease study data and methods, we also quantified the burden of disease related to high body-mass index (BMI), according to age, sex, cause, and BMI in 195 countries between 1990 and 2015. RESULTS In 2015, a total of 107.7 million children and 603.7 million adults were obese. Since 1980, the prevalence of obesity has doubled in more than 70 countries and has continuously increased in most other countries. Although the prevalence of obesity among children has been lower than that among adults, the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity. High BMI accounted for 4.0 million deaths globally, nearly 40% of which occurred in persons who were not obese. More than two thirds of deaths related to high BMI were due to cardiovascular disease. The disease burden related to high BMI has increased since 1990; however, the rate of this increase has been attenuated owing to decreases in underlying rates of death from cardiovascular disease. CONCLUSIONS The rapid increase in the prevalence and disease burden of elevated BMI highlights the need for continued focus on surveillance of BMI and identification, implementation, and evaluation of evidence-based interventions to address this problem. 

  • 3.
    Andersen, Peter M.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hempel, Maja
    Santer, René
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Tsiakas, Konstantinos
    Johannsen, Jessika
    Volk, Alexander E.
    Bierhals, Tatjana
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Phenotype in an Infant with SOD1 Homozygous Truncating Mutation2019In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, no 5, p. 486-488Article in journal (Refereed)
  • 4. Beer, Tomasz M
    et al.
    Armstrong, Andrew J
    Rathkopf, Dana E
    Loriot, Yohann
    Sternberg, Cora N
    Higano, Celestia S
    Iversen, Peter
    Bhattacharya, Suman
    Carles, Joan
    Chowdhury, Simon
    Davis, Ian D
    de Bono, Johann S
    Evans, Christopher P
    Fizazi, Karim
    Joshua, Anthony M
    Kim, Choung-Soo
    Kimura, Go
    Mainwaring, Paul
    Mansbach, Harry
    Miller, Kurt
    Noonberg, Sarah B
    Perabo, Frank
    Phung, De
    Saad, Fred
    Scher, Howard I
    Taplin, Mary-Ellen
    Venner, Peter M
    Tombal, Bertrand
    Enzalutamide in metastatic prostate cancer before chemotherapy.2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.

    METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.

    RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.

    CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

  • 5. Chinot, Olivier L.
    et al.
    Wick, Wolfgang
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Saran, Frank
    Nishikawa, Ryo
    Carpentier, Antoine F.
    Hoang-Xuan, Khe
    Kavan, Petr
    Cernea, Dana
    Brandes, Alba A.
    Hilton, Magalie
    Abrey, Lauren
    Cloughesy, Timothy
    Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, no 8, p. 709-722Article in journal (Refereed)
    Abstract [en]

    BackgroundStandard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. MethodsWe randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival. ResultsA total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%). ConclusionsThe addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo. 

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  • 6. Crosby, Jacy
    et al.
    Peloso, Gina M.
    Auer, Paul L.
    Crosslin, David R.
    Stitziel, Nathan O.
    Lange, Leslie A.
    Lu, Yingchang
    Tang, Zheng-zheng
    Zhang, He
    Hindy, George
    Masca, Nicholas
    Stirrups, Kathleen
    Kanoni, Stavroula
    Do, Ron
    Jun, Goo
    Hu, Youna
    Kang, Hyun Min
    Xue, Chenyi
    Goel, Anuj
    Farrall, Martin
    Duga, Stefano
    Merlini, Pier Angelica
    Asselta, Rosanna
    Girelli, Domenico
    Olivieri, Oliviero
    Martinelli, Nicola
    Yin, Wu
    Reilly, Dermot
    Speliotes, Elizabeth
    Fox, Caroline S.
    Hveem, Kristian
    Holmen, Oddgeir L.
    Nikpay, Majid
    Farlow, Deborah N.
    Assimes, Themistocles L.
    Franceschini, Nora
    Robinson, Jennifer
    North, Kari E.
    Martin, Lisa W.
    DePristo, Mark
    Gupta, Namrata
    Andersson Escher, Stefan
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Medicine, Skellefteå Hospital, Skellefteå .
    Van Zuydam, Natalie
    Palmer, Colin N. A.
    Wareham, Nicholas
    Koch, Werner
    Meitinger, Thomas
    Peters, Annette
    Lieb, Wolfgang
    Erbel, Raimund
    Konig, Inke R.
    Kruppa, Jochen
    Degenhardt, Franziska
    Gottesman, Omri
    Bottinger, Erwin P.
    O'Donnell, Christopher J.
    Psaty, Bruce M.
    Ballantyne, Christie M.
    Abecasis, Goncalo
    Ordovas, Jose M.
    Melander, Olle
    Watkins, Hugh
    Orho-Melander, Marju
    Ardissino, Diego
    Loos, Ruth J. F.
    McPherson, Ruth
    Willer, Cristen J.
    Erdmann, Jeanette
    Hall, Alistair S.
    Samani, Nilesh J.
    Deloukas, Panos
    Schunkert, Heribert
    Wilson, James G.
    Kooperberg, Charles
    Rich, Stephen S.
    Tracy, Russell P.
    Lin, Dan-Yu
    Altshuler, David
    Gabriel, Stacey
    Nickerson, Deborah A.
    Jarvik, Gail P.
    Cupples, L. Adrienne
    Reiner, Alex P.
    Boerwinkle, Eric
    Kathiresan, Sekar
    Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 1, p. 22-31Article in journal (Refereed)
    Abstract [en]

    Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G -> A and IVS3+1G -> T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1x10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8x10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4x10(-6)). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)

  • 7.
    Ekbom, K.
    et al.
    Söder Hospital, Karolinska Institute, Stockholm, Sweden.
    Waldenlind, E.
    Söder Hospital, Karolinska Institute, Stockholm, Sweden.
    Richard, Levi
    Söder Hospital, Karolinska Institute, Stockholm, Sweden.
    Andersson, B.
    Gãvle Hospital, Gãvle, Sweden.
    Boivie, J.
    University Hospital, Linköping, Sweden.
    Dizdar, N.
    University Hospital, Linköping, Sweden.
    Bousser, M.G.
    Hôpital St. Antoine, Paris, France.
    Tehindrazanirivelo, A.
    Hôpital St. Antoine, Paris, France.
    Lutz, G.
    Hôpital St. Antoine, Paris, France.
    Hannerz, J.
    Karolinska Hospital, Karolinska Institute, Stockholm, Sweden.
    Hardebo, J.E.
    University Hospital, Lund. Sweden.
    Henry, P.
    Hôpital Pellegrin—Tripode, Bordeaux, France.
    Rosazza, M.
    Hôpital Pellegrin—Tripode, Bordeaux, France.
    Krabbe, A.
    Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
    Kinnman, J.
    Halmstad Hospital, Halmstad, Sweden.
    Persson, L.I.
    Sahlgrenska Hospital, University of University of Gothenburg, Gothenburg, Sweden.
    Prusinski, A.
    Neurology Clinic, Medical Academy, Lodz, Poland.
    Durko, A.
    Neurology Clinic, Medical Academy, Lodz, Poland.
    Kozubski, W.
    Neurology Clinic, Medical Academy, Lodz, Poland.
    Rozniecki, M.D.
    Neurology Clinic, Medical Academy, Lodz, Poland.
    Wysocka-Bakowska, M.M.
    Neurology Clinic, Medical Medical Academy, Warsaw, Poland.
    Cole, J.A.
    Glaxo Group Research Ltd., Greenford, Middlesex. United Kingdom.
    Patel, P.
    Glaxo Group Research Ltd., Greenford, Middlesex. United Kingdom.
    Pilgrim, AJ.
    Glaxo Group Research Ltd., Greenford, Middlesex. United Kingdom.
    Winter, O'B.
    Glaxo Group Research Ltd., Greenford, Middlesex. United Kingdom.
    Donoghue, S.
    Glaxo Group Research Ltd., Greenford, Middlesex. United Kingdom.
    Treatment of acute cluster headache with sumatriptan1991In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, no 325, p. 322-326Article in journal (Refereed)
  • 8. Erlinge, D.
    et al.
    Omerovic, E.
    Frobert, O.
    Linder, Robert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Danielewicz, M.
    Hamid, M.
    Swahn, E.
    Henareh, L.
    Wagner, H.
    Hårdhammar, P.
    Sjögren, I.
    Stewart, J.
    Grimfjärd, P.
    Jensen, J.
    Aasa, M.
    Robertsson, L.
    Lindroos, P.
    Haupt, J.
    Wikström, H.
    Ulvenstam, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Bhiladvala, P.
    Lindvall, B.
    Lundin, A.
    Tödt, T.
    Ioanes, D.
    Råmunddal, T.
    Kellerth, T.
    Zagozdzon, L.
    Götberg, M.
    Andersson, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Angerås, O.
    Östlund, O.
    Lagerqvist, B.
    Held, C.
    Wallentin, L.
    Scherstén, F.
    Eriksson, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Koul, S.
    James, S.
    Bivalirudin versus heparin monotherapy in myocardial infarction2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 12, p. 1132-1142Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The comparative efficacy of various anticoagulation strategies has not been clearly established in patients with acute myocardial infarction who are undergoing percutaneous coronary intervention (PCI) according to current practice, which includes the use of radial-artery access for PCI and administration of potent P2Y 12 inhibitors without the planned use of glycoprotein IIb/IIIa inhibitors.

    METHODS In this multicenter, randomized, registry-based, open-label clinical trial, we enrolled patients with either ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) who were undergoing PCI and receiving treatment with a potent P2Y(12) inhibitor (ticagrelor, prasugrel, or cangrelor) without the planned use of glycoprotein IIb/IIIa inhibitors. The patients were randomly assigned to receive bivalirudin or heparin during PCI, which was performed predominantly with the use of radial-artery access. The primary end point was a composite of death from any cause, myocardial infarction, or major bleeding during 180 days of follow-up.

    RESULTS A total of 6006 patients (3005 with STEMI and 3001 with NSTEMI) were enrolled in the trial. At 180 days, a primary end-point event had occurred in 12.3% of the patients (369 of 3004) in the bivalirudin group and in 12.8% (383 of 3002) in the heparin group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.10; P = 0.54). The results were consistent between patients with STEMI and those with NSTEMI and across other major subgroups. Myocardial infarction occurred in 2.0% of the patients in the bivalirudin group and in 2.4% in the heparin group (hazard ratio, 0.84; 95% CI, 0.60 to 1.19; P = 0.33), major bleeding in 8.6% and 8.6%, respectively (hazard ratio, 1.00; 95% CI, 0.84 to 1.19; P = 0.98), definite stent thrombosis in 0.4% and 0.7%, respectively (hazard ratio, 0.54; 95% CI, 0.27 to 1.10; P = 0.09), and death in 2.9% and 2.8%, respectively (hazard ratio, 1.05; 95% CI, 0.78 to 1.41; P = 0.76).

    CONCLUSIONS Among patients undergoing PCI for myocardial infarction, the rate of the composite of death from any cause, myocardial infarction, or major bleeding was not lower among those who received bivalirudin than among those who received heparin monotherapy. (Funded by the Swedish Heart-Lung Foundation and others; VALIDATE-SWEDEHEART Clinical-TrialsRegister.eu number, 2012-005260-10; ClinicalTrials.gov number, NCT02311231.)

  • 9.
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Childhood obesity, other cardiovascular risk factors, and premature death2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 362, no 13, p. 1840-1842Article, book review (Other academic)
  • 10.
    Franks, Paul W
    et al.
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Hanson, Robert L
    Knowler, William C
    Sievers, Maurice L
    Bennett, Peter H
    Looker, Helen C
    Childhood obesity, other cardiovascular risk factors, and premature death.2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 362, no 6, p. 485-493Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The effect of childhood risk factors for cardiovascular disease on adult mortality is poorly understood. METHODS: In a cohort of 4857 American Indian children without diabetes (mean age, 11.3 years; 12,659 examinations) who were born between 1945 and 1984, we assessed whether body-mass index (BMI), glucose tolerance, and blood pressure and cholesterol levels predicted premature death. Risk factors were standardized according to sex and age. Proportional-hazards models were used to assess whether each risk factor was associated with time to death occurring before 55 years of age. Models were adjusted for baseline age, sex, birth cohort, and Pima or Tohono O'odham Indian heritage. RESULTS: There were 166 deaths from endogenous causes (3.4% of the cohort) during a median follow-up period of 23.9 years. Rates of death from endogenous causes among children in the highest quartile of BMI were more than double those among children in the lowest BMI quartile (incidence-rate ratio, 2.30; 95% confidence interval [CI], 1.46 to 3.62). Rates of death from endogenous causes among children in the highest quartile of glucose intolerance were 73% higher than those among children in the lowest quartile (incidence-rate ratio, 1.73; 95% CI, 1.09 to 2.74). No significant associations were seen between rates of death from endogenous or external causes and childhood cholesterol levels or systolic or diastolic blood-pressure levels on a continuous scale, although childhood hypertension was significantly associated with premature death from endogenous causes (incidence-rate ratio, 1.57; 95% CI, 1.10 to 2.24). CONCLUSIONS: Obesity, glucose intolerance, and hypertension in childhood were strongly associated with increased rates of premature death from endogenous causes in this population. In contrast, childhood hypercholesterolemia was not a major predictor of premature death from endogenous causes.

  • 11. Frobert, Ole
    et al.
    Lagerqvist, Bo
    Olivecrona, Goran K.
    Omerovic, Elmir
    Gudnason, Thorarinn
    Maeng, Michael
    Aasa, Mikael
    Angeras, Oskar
    Calais, Fredrik
    Danielewicz, Mikael
    Erlinge, David
    Hellsten, Lars
    Jensen, Ulf
    Johansson, Agneta C.
    Karegren, Amra
    Nilsson, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Heart Centrum.
    Robertson, Lotta
    Sandhall, Lennart
    Sjogren, Iwar
    Ostlund, Ollie
    Harnek, Jan
    James, Stefan K.
    Thrombus Aspiration during ST-Segment Elevation Myocardial Infarction2013In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 369, no 17, p. 1587-1597Article in journal (Refereed)
    Abstract [en]

    BackgroundThe clinical effect of routine intracoronary thrombus aspiration before primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) is uncertain. We aimed to evaluate whether thrombus aspiration reduces mortality. MethodsWe conducted a multicenter, prospective, randomized, controlled, open-label clinical trial, with enrollment of patients from the national comprehensive Swedish Coronary Angiography and Angioplasty Registry (SCAAR) and end points evaluated through national registries. A total of 7244 patients with STEMI undergoing PCI were randomly assigned to manual thrombus aspiration followed by PCI or to PCI only. The primary end point was all-cause mortality at 30 days. ResultsNo patients were lost to follow-up. Death from any cause occurred in 2.8% of the patients in the thrombus-aspiration group (103 of 3621), as compared with 3.0% in the PCI-only group (110 of 3623) (hazard ratio, 0.94; 95% confidence interval [CI], 0.72 to 1.22; P=0.63). The rates of hospitalization for recurrent myocardial infarction at 30 days were 0.5% and 0.9% in the two groups, respectively (hazard ratio, 0.61; 95% CI, 0.34 to 1.07; P=0.09), and the rates of stent thrombosis were 0.2% and 0.5%, respectively (hazard ratio, 0.47; 95% CI, 0.20 to 1.02; P=0.06). There were no significant differences between the groups with respect to the rate of stroke or neurologic complications at the time of discharge (P=0.87). The results were consistent across all major prespecified subgroups, including subgroups defined according to thrombus burden and coronary flow before PCI. ConclusionsRoutine thrombus aspiration before PCI as compared with PCI alone did not reduce 30-day mortality among patients with STEMI. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT01093404.)

  • 12.
    Gamble, Carrol
    et al.
    University of Liverpool, Liverpool, UK.
    Persson, Christina
    University of Gothenburg, Gothenburg, Sweden.
    Willadsen, Elisabeth
    University of Copenhagen, Copenhagen, Denmark.
    Albery, Liz
    Bristol Dental Hospital, Bristol, UK.
    Soegaard Andersen, Helene
    Copenhagen Cleft Palate Center, Copenhagen, Denmark.
    Zattoni Antoneli, Melissa
    University of São Paulo, Bauru, Brazil.
    Appelqvist, Malin
    Uppsala University Hospital, Uppsala, Sweden.
    Aukner, Ragnhild
    Statped, Oslo, Norway.
    Bodling, Pia
    Linköping University Hospital, Linköping, Sweden.
    Bowden, Melanie
    Manchester University NHS Foundation Trust, Manchester, UK.
    Brunnegård, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Cairns, Gillian
    Royal Hospital for Sick Children, Edinburgh, UK.
    Calladine, Samantha
    Northern and Yorkshire Regional Cleft Lip and Palate Service, Leeds, UK.
    Campbell, Linsay
    Cleft Care Scotland, Glasgow, UK.
    Clayton-Smith, Jill
    University of Manchester, Manchester, UK.
    Cooper, Rachael
    University of Liverpool, Liverpool, UK.
    Conroy, Elizabeth
    University of Liverpool, Liverpool, UK.
    El-Angbawi, Ahmed
    University of Manchester, Manchester, UK.
    Kildegaard Emborg, Berit
    Cleft Palate Center, Aarhus, Denmark.
    Enfält Wikman, Josefin
    Norrlands University Hospital, Umeå, Sweden.
    Fitzpatrick, Beth
    Birmingham Children’s Hospital, Birmingham, UK.
    Fukushiro, Ana Paula
    University of São Paulo, Bauru, Brazil.
    Guedes de Azevedo Bento Gonçalves, Cristina
    University of São Paulo, Bauru, Brazil.
    Havstam, Christina
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Hvistendahl, Anne Katherine
    Statped, Oslo, Norway.
    Dahl Jorgensen, Line
    University of Copenhagen, Copenhagen, Denmark; Copenhagen Cleft Palate Center, Copenhagen, Denmark.
    Klinto, Kristina
    Skåne University Hospital, Malmö, Sweden.
    Berntsen Kvinnsland, Marit
    Statped, Oslo, Norway.
    Larham, Catriona
    Leeds General Infirmary, UK.
    Lemvik, Jorunn
    Statped, Oslo, Norway.
    Leturgie, Louise
    Cleft Palate Center, Aarhus, Denmark.
    Liljerehn, Eva
    Uppsala University Hospital, Uppsala, Sweden.
    Lodge, Natalie
    Royal Hospital for Sick Children, Liverpool, UK.
    Lohmander, Anette
    Karolinska Institutet, Solna, Sweden.
    McMahon, Siobhan
    Alder Hey Children’s NHS Foundation Trust, UK.
    Mehendale, Felicity
    University of Edinburgh, Edinburgh, UK.
    Coracine Miguel, Haline
    University of São Paulo, Bauru, Brazil.
    Moe, Marianne
    Statped Sørøst, Oslo, Norway.
    Bogh Nielsen, Joan
    Cleft Palate Center, Aarhus, Denmark.
    Nyberg, Jill
    Karolinska Institutet, Solna, Sweden.
    Pedersen, Nina-Helen
    Statped Vest, Bergen, Norway.
    Phippen, Ginette
    Salisbury District Hospital, Salisbury, UK.
    Alvarez Piazentin-Penna, Silvia Helena
    University of São Paulo, Bauru, Brazil.
    Patrick, Kathryn
    Manchester University NHS Foundation Trust, Manchester, UK.
    Pliskin, Lindsay
    University of Liverpool, Liverpool, UK.
    Rigby, Lucy
    Royal Victoria Infirmary, Newcastle upon Tyne, UK.
    Semb, Gunvor
    University of Manchester, Manchester, UK.
    Southby, Lucy
    Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Sporre, Maria
    Skåne University Hospital, Malmö, Sweden.
    Björkman Taleman, Ann-Sofie
    Linköping University Hospital, Linköping, Sweden.
    Tangstad, Jorid
    Statped Vest, Bergen, Norway.
    Kiemle Trindade, Inge Elly
    University of São Paulo, Bauru, Brazil.
    Underwood, Imogen
    Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK.
    van Eeden, Stephanie
    Royal Victoria Infirmary, Newcastle upon Tyne, UK.
    Raud Westberg, Liisi
    Karolinska University Hospital, Stockholm, Sweden.
    Williamson, Paula Ruth
    University of Liverpool, Liverpool, UK.
    Paciello Yamashita, Renata
    University of São Paulo, Bauru, Brazil.
    Munro, Kevin
    University of Manchester, Liverpool, UK.
    Walsh, Tanya
    University of Manchester, Manchester, UK.
    Shaw, William
    University of Manchester, Manchester, UK.
    Timing of primary surgery for cleft palate2023In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 389, no 9, p. 795-807Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Among infants with isolated cleft palate, whether primary surgery at 6 months of age is more beneficial than surgery at 12 months of age with respect to speech outcomes, hearing outcomes, dentofacial development, and safety is unknown.

    METHODS: We randomly assigned infants with nonsyndromic isolated cleft palate, in a 1:1 ratio, to undergo standardized primary surgery at 6 months of age (6-month group) or at 12 months of age (12-month group) for closure of the cleft. Standardized assessments of quality-checked video and audio recordings at 1, 3, and 5 years of age were performed independently by speech and language therapists who were unaware of the trial-group assignments. The primary outcome was velopharyngeal insufficiency at 5 years of age, defined as a velopharyngeal composite summary score of at least 4 (scores range from 0 to 6, with higher scores indicating greater severity). Secondary outcomes included speech development, postoperative complications, hearing sensitivity, dentofacial development, and growth.

    RESULTS: We randomly assigned 558 infants at 23 centers across Europe and South America to undergo surgery at 6 months of age (281 infants) or at 12 months of age (277 infants). Speech recordings from 235 infants (83.6%) in the 6-month group and 226 (81.6%) in the 12-month group were analyzable. Insufficient velopharyngeal function at 5 years of age was observed in 21 of 235 infants (8.9%) in the 6-month group as compared with 34 of 226 (15.0%) in the 12-month group (risk ratio, 0.59; 95% confidence interval, 0.36 to 0.99; P = 0.04). Postoperative complications were infrequent and similar in the 6-month and 12-month groups. Four serious adverse events were reported (three in the 6-month group and one in the 12-month group) and had resolved at follow-up.

    CONCLUSIONS: Medically fit infants who underwent primary surgery for isolated cleft palate in adequately resourced settings at 6 months of age were less likely to have velopharyngeal insufficiency at the age of 5 years than those who had surgery at 12 months of age. 

  • 13.
    Hallberg, Bengt
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Palmer, Ruth H
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Crizotinib: latest champion in the cancer wars?2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 363, no 18, p. 1760-1762Article in journal (Refereed)
  • 14.
    Hariz, Marwan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Okun, Michael S.
    University of Florida, FL, Gainesville, Puerto Rico.
    Vitek, Jerrold L.
    University of Minnesota, MN, Minneapolis, United States.
    Focused ultrasound ablation in Parkinson's disease2023In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 388, no 19, p. 1822-1823Article in journal (Other academic)
  • 15. Holman, Rury R.
    et al.
    Haffner, Steven M.
    McMurray, John J.
    Bethel, M. Angelyn
    Holzhauer, Bjoern
    Hua, Tsushung A.
    Belenkov, Yuri
    Boolell, Mitradev
    Buse, John B.
    Buckley, Brendan M.
    Chacra, Antonio R.
    Chiang, Fu-Tien
    Charbonnel, Bernard
    Chow, Chun-Chung
    Davies, Melanie J.
    Deedwania, Prakash
    Diem, Peter
    Einhorn, Daniel
    Fonseca, Vivian
    Fulcher, Gregory R.
    Gaciong, Zbigniew
    Gaztambide, Sonia
    Giles, Thomas
    Horton, Edward
    Ilkova, Hasan
    Jenssen, Trond
    Kahn, Steven E.
    Krum, Henry
    Laakso, Markku
    Leiter, Lawrence A.
    Levitt, Naomi S.
    Mareev, Viacheslav
    Martinez, Felipe
    Masson, Chantal
    Mazzone, Theodore
    Meaney, Eduardo
    Nesto, Richard
    Pan, Changyu
    Prager, Rudolf
    Raptis, Sotirios A.
    Rutten, Guy E. H. M.
    Sandström, Herbert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Schaper, Frank
    Scheen, Andre
    Schmitz, Ole
    Sinay, Isaac
    Soska, Vladimir
    Stender, Steen
    Tamas, Gyula
    Tognoni, Gianni
    Tuomilehto, Jaako
    Villamil, Alberto S.
    Vozar, Juraj
    Califf, Robert M.
    Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 362, no 16, p. 1463-1476Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P = 0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P = 0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P = 0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

  • 16. Hom, Geoffrey
    et al.
    Graham, Robert R
    Modrek, Barmak
    Taylor, Kimberly E
    Ortmann, Ward
    Garnier, Sophie
    Lee, Annette T
    Chung, Sharon A
    Ferreira, Ricardo C
    Pant, P V Krishna
    Ballinger, Dennis G
    Kosoy, Roman
    Demirci, F Yesim
    Kamboh, M Ilyas
    Kao, Amy H
    Tian, Chao
    Gunnarsson, Iva
    Bengtsson, Anders A
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Petri, Michelle
    Manzi, Susan
    Seldin, Michael F
    Rönnblom, Lars
    Syvänen, Ann-Christine
    Criswell, Lindsey A
    Gregersen, Peter K
    Behrens, Timothy W
    Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX.2008In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 358, no 9, p. 900-909Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4are established susceptibility genes; there is strong evidence for the existence of additional risk loci.

    METHODS: We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.

    RESULTS: Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case–control series (rs13277113; odds ratio, 1.39; P=1×10−10) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3×10−11).

  • 17. Kaptoge, Stephen
    et al.
    Di Angelantonio, Emanuele
    Pennells, Lisa
    Wood, Angela M.
    White, Ian R.
    Gao, Pei
    Walker, Matthew
    Thompson, Alexander
    Sarwar, Nadeem
    Caslake, Muriel
    Butterworth, Adam S.
    Amouyel, Philippe
    Assmann, Gerd
    Bakker, Stephan J. L.
    Barr, Elizabeth L. M.
    Barrett-Connor, Elizabeth
    Benjamin, Emelia J.
    Bjorkelund, Cecilia
    Brenner, Hermann
    Brunner, Eric
    Clarke, Robert
    Cooper, Jackie A.
    Cremer, Peter
    Cushman, Mary
    Dagenais, Gilles R.
    D'Agostino, Ralph B., Sr.
    Dankner, Rachel
    Davey-Smith, George
    Deeg, Dorly
    Dekker, Jacqueline M.
    Engstrom, Gunnar
    Folsom, Aaron R.
    Fowkes, F. Gerry R.
    Gallacher, John
    Gaziano, J. Michael
    Giampaoli, Simona
    Gillum, Richard F.
    Hofman, Albert
    Howard, Barbara V.
    Ingelsson, Erik
    Iso, Hiroyasu
    Jorgensen, Torben
    Kiechl, Stefan
    Kitamura, Akihiko
    Kiyohara, Yutaka
    Koenig, Wolfgang
    Kromhout, Daan
    Kuller, Lewis H.
    Lawlor, Debbie A.
    Meade, Tom W.
    Nissinen, Aulikki
    Nordestgaard, Borge G.
    Onat, Altan
    Panagiotakos, Demosthenes B.
    Psaty, Bruce M.
    Rodriguez, Beatriz
    Rosengren, Annika
    Salomaa, Veikko
    Kauhanen, Jussi
    Salonen, Jukka T.
    Shaffer, Jonathan A.
    Shea, Steven
    Ford, Ian
    Stehouwer, Coen D. A.
    Strandberg, Timo E.
    Tipping, Robert W.
    Tosetto, Alberto
    Wassertheil-Smoller, Sylvia
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Westendorp, Rudi G.
    Whincup, Peter H.
    Wilhelmsen, Lars
    Woodward, Mark
    Lowe, Gordon D. O.
    Wareham, Nicholas J.
    Khaw, Kay-Tee
    Sattar, Naveed
    Packard, Chris J.
    Gudnason, Vilmundur
    Ridker, Paul M.
    Pepys, Mark B.
    Thompson, Simon G.
    Danesh, John
    C-Reactive Protein, Fibrinogen, and Cardiovascular Disease Prediction2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 14, p. 1310-1320Article in journal (Refereed)
    Abstract [en]

    Background There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. Methods We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. Results The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P < 0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (< 10%), " intermediate" (10% to < 20%), and "high" (>= 20%) (P < 0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of >= 20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years. Conclusions In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.)

  • 18. Lagerqvist, Bo
    et al.
    Fröbert, Ole
    Olivecrona, Göran K.
    Gudnason, Thórarinn
    Maeng, Michael
    Alström, Patrik
    Andersson, Jonas
    Umeå University Hospital.
    Calais, Fredrik
    Carlsson, Jörg
    Collste, Olov
    Götberg, Matthias
    Hårdhammar, Peter
    Ioanes, Dan
    Kallryd, Anders
    Linder, Rickard
    Lundin, Anders
    Odenstedt, Jacob
    Omerovic, Elmir
    Puskar, Verner
    Tödt, Tim
    Zelleroth, Eva
    Östlund, Ollie
    James, Stefan K.
    Outcomes 1 Year after Thrombus Aspiration for Myocardial Infarction2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 12, p. 1111-1120Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Routine intracoronary thrombus aspiration before primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) has not been proved to reduce short-term mortality. We evaluated clinical outcomes at 1 year after thrombus aspiration. METHODS We randomly assigned 7244 patients with STEMI to undergo manual thrombus aspiration followed by PCI or to undergo PCI alone, in a registry-based, randomized clinical trial. The primary end point of all-cause mortality at 30 days has been reported previously. Death from any cause at 1 year was a prespecified secondary end point of the trial. RESULTS No patients were lost to follow-up. Death from any cause occurred in 5.3% of the patients (191 of 3621 patients) in the thrombus-aspiration group, as compared with 5.6% (202 of 3623) in the PCI-only group (hazard ratio, 0.94; 95% confidence interval [CI], 0.78 to 1.15; P = 0.57). Rehospitalization for myocardial infarction at 1 year occurred in 2.7% and 2.7% of the patients, respectively (hazard ratio, 0.97; 95% CI, 0.73 to 1.28; P = 0.81), and stent thrombosis in 0.7% and 0.9%, respectively (hazard ratio, 0.84; 95% CI, 0.50 to 1.40; P = 0.51). The composite of death from any cause, rehospitalization for myocardial infarction, or stent thrombosis occurred in 8.0% and 8.5% of the patients, respectively (hazard ratio, 0.94; 95% CI, 0.80 to 1.11; P = 0.48). The results were consistent across all the major subgroups, including grade of thrombus burden and coronary flow before PCI. CONCLUSIONS Routine thrombus aspiration before PCI in patients with STEMI did not reduce the rate of death from any cause or the composite of death from any cause, rehospitalization for myocardial infarction, or stent thrombosis at 1 year.

  • 19. Lichtenstein, Paul
    et al.
    Halldner, Linda
    Zetterqvist, Johan
    Sjölander, Arvid
    Serlachius, Eva
    Fazel, Seena
    Långström, Niklas
    Larsson, Henrik
    Medication for attention deficit-hyperactivity disorder and criminality.2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 21, p. 2006-14Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Attention deficit-hyperactivity disorder (ADHD) is a common disorder that has been associated with criminal behavior in some studies. Pharmacologic treatment is available for ADHD and may reduce the risk of criminality.

    METHODS: Using Swedish national registers, we gathered information on 25,656 patients with a diagnosis of ADHD, their pharmacologic treatment, and subsequent criminal convictions in Sweden from 2006 through 2009. We used stratified Cox regression analyses to compare the rate of criminality while the patients were receiving ADHD medication, as compared with the rate for the same patients while not receiving medication.

    RESULTS: As compared with nonmedication periods, among patients receiving ADHD medication, there was a significant reduction of 32% in the criminality rate for men (adjusted hazard ratio, 0.68; 95% confidence interval [CI], 0.63 to 0.73) and 41% for women (hazard ratio, 0.59; 95% CI, 0.50 to 0.70). The rate reduction remained between 17% and 46% in sensitivity analyses among men, with factors that included different types of drugs (e.g., stimulant vs. nonstimulant) and outcomes (e.g., type of crime).

    CONCLUSIONS: Among patients with ADHD, rates of criminality were lower during periods when they were receiving ADHD medication. These findings raise the possibility that the use of medication reduces the risk of criminality among patients with ADHD. (Funded by the Swedish Research Council and others.).

  • 20. Liu, Cong
    et al.
    Chen, Renjie
    Sera, Francesco
    Vicedo-Cabrera, Ana M
    Guo, Yuming
    Tong, Shilu
    Coelho, Micheline S Z S
    Saldiva, Paulo H N
    Lavigne, Eric
    Matus, Patricia
    Valdes Ortega, Nicolas
    Osorio Garcia, Samuel
    Pascal, Mathilde
    Stafoggia, Massimo
    Scortichini, Matteo
    Hashizume, Masahiro
    Honda, Yasushi
    Hurtado-Díaz, Magali
    Cruz, Julio
    Nunes, Baltazar
    Teixeira, João P
    Kim, Ho
    Tobias, Aurelio
    Íñiguez, Carmen
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Åström, Christofer
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Ragettli, Martina S
    Guo, Yue-Leon
    Chen, Bing-Yu
    Bell, Michelle L
    Wright, Caradee Y
    Scovronick, Noah
    Garland, Rebecca M
    Milojevic, Ai
    Kyselý, Jan
    Urban, Aleš
    Orru, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health. The Institute of Family Medicine and Public Health, University of Tartu, Tartu, Estonia.
    Indermitte, Ene
    Jaakkola, Jouni J K
    Ryti, Niilo R I
    Katsouyanni, Klea
    Analitis, Antonis
    Zanobetti, Antonella
    Schwartz, Joel
    Chen, Jianmin
    Wu, Tangchun
    Cohen, Aaron
    Gasparrini, Antonio
    Kan, Haidong
    Ambient Particulate Air Pollution and Daily Mortality in 652 Cities2019In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, no 8, p. 705-715Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The systematic evaluation of the results of time-series studies of air pollution is challenged by differences in model specification and publication bias.

    METHODS: We evaluated the associations of inhalable particulate matter (PM) with an aerodynamic diameter of 10 μm or less (PM10) and fine PM with an aerodynamic diameter of 2.5 μm or less (PM2.5) with daily all-cause, cardiovascular, and respiratory mortality across multiple countries or regions. Daily data on mortality and air pollution were collected from 652 cities in 24 countries or regions. We used overdispersed generalized additive models with random-effects meta-analysis to investigate the associations. Two-pollutant models were fitted to test the robustness of the associations. Concentration-response curves from each city were pooled to allow global estimates to be derived.

    RESULTS: On average, an increase of 10 μg per cubic meter in the 2-day moving average of PM10 concentration, which represents the average over the current and previous day, was associated with increases of 0.44% (95% confidence interval [CI], 0.39 to 0.50) in daily all-cause mortality, 0.36% (95% CI, 0.30 to 0.43) in daily cardiovascular mortality, and 0.47% (95% CI, 0.35 to 0.58) in daily respiratory mortality. The corresponding increases in daily mortality for the same change in PM2.5 concentration were 0.68% (95% CI, 0.59 to 0.77), 0.55% (95% CI, 0.45 to 0.66), and 0.74% (95% CI, 0.53 to 0.95). These associations remained significant after adjustment for gaseous pollutants. Associations were stronger in locations with lower annual mean PM concentrations and higher annual mean temperatures. The pooled concentration-response curves showed a consistent increase in daily mortality with increasing PM concentration, with steeper slopes at lower PM concentrations.

    CONCLUSIONS: Our data show independent associations between short-term exposure to PM10 and PM2.5 and daily all-cause, cardiovascular, and respiratory mortality in more than 600 cities across the globe. These data reinforce the evidence of a link between mortality and PM concentration established in regional and local studies. (Funded by the National Natural Science Foundation of China and others.).

  • 21.
    Löfgren, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nordin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ibingira, Charles
    Makerere University.
    Matovu, Alphonsus
    Makerere University.
    Galiwango, Edward
    Makerere University.
    Wladis, Andreas
    Karolinska Institutet.
    A Randomized Trial of Low-Cost Mesh in Groin Hernia Repair2016In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 374, no 2, p. 146-153Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The most effective method for repair of a groin hernia involves the use of a syn-thetic mesh, but this type of mesh is unaffordable for many patients in low- and middle-income countries. Sterilized mosquito meshes have been used as a lower-cost alternative but have not been rigorously studied.METHODS: We performed a double-blind, randomized, controlled trial comparing low-cost mesh with commercial mesh (both lightweight) for the repair of a groin hernia in adult men in eastern Uganda who had primary, unilateral, reducible groin hernias. Surgery was performed by four qualified surgeons. The primary outcomes were hernia recurrence at 1 year and postoperative complications.RESULTS: A total of 302 patients were included in the study. The follow-up rate was 97.3% after 2 weeks and 95.6% after 1 year. Hernia recurred in 1 patient (0.7%) assigned to the low-cost mesh and in no patients assigned to the commercial mesh (abso-lute risk difference, 0.7 percentage points; 95% confidence interval [CI], −1.2 to 2.6; P = 1.0). Postoperative complications occurred in 44 patients (30.8%) assigned to the low-cost mesh and in 44 patients (29.7%) assigned to the commercial mesh (absolute risk difference, 1.0 percentage point; 95% CI, −9.5 to 11.6; P = 1.0).CONCLUSIONS: Rates of hernia recurrence and postoperative complications did not differ signifi-cantly between men undergoing hernia repair with low-cost mesh and those un-dergoing hernia repair with commercial mesh.

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  • 22.
    Magnussen, Christina
    et al.
    Center for Population Health Innovation, University Heart and Vascular Center Hamburg, Germany; University Medical Center Hamburg Eppendorf, Germany; German Center for Cardiovascular Research (DZHK) Partner Site Hamburg Kiel Lübeck, Germany.
    Ojeda, Francisco M.
    Center for Population Health Innovation, University Heart and Vascular Center Hamburg, Germany; University Medical Center Hamburg Eppendorf, Germany.
    Leong, Darryl P.
    Department of Medicine (Cardiology), McMaster University, Hamilton, Canada.
    Alegre-Diaz, Jesus
    Experimental Medicine Research Unit, School of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.
    Amouyel, Philippe
    Université de Lille, Inserm, Centre Hospitalier University de Lille, Institut Pasteur de Lille, UMR1167 RID-AGE Risk Factors and Molecular Determinants of Aging-Related Diseases, Epidemiology and Public Health Department, Lille, France.
    Aviles-Santa, Larissa
    Division of Clinical and Health Services Research, National Institute on Minority Health and Health Disparities, National Institutes of Health, MD, Bethesda, United States.
    De Bacquer, Dirk
    Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.
    Ballantyne, Christie M.
    Department of Medicine, Baylor College of Medicine, TX, Houston, United States.
    Bernabé-Ortiz, Antonio
    Cronicas Center of Excellence in Chronic Diseases, Universidad Peruana Cayetano Heredia, Lima, Peru.
    Bobak, Martin
    Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Brenner, Hermann
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, and Network Aging Research, Heidelberg University, Heidelberg, Germany.
    Carrillo-Larco, Rodrigo M.
    Emory Global Diabetes Research Center, Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, United States.
    De Lemos, James
    Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, TX, Dallas, United States.
    Dobson, Annette
    School of Public Health, University of Queensland, Brisbane, Australia.
    Dörr, Marcus
    Department of Internal Medicine B, University Medicine Greifswald, Dzhk Partner Site Greifswald, Greifswald, Germany.
    Donfrancesco, Chiara
    Department of Cardiovascular and Endocrine Metabolic Diseases and Aging, Istituto Superiore di Sanità, Rome, Italy.
    Drygas, Wojciech
    Department of Epidemiology, Cardiovascular Disease Prevention and Health Promotion, National Institute of Cardiology, Lazarski University, Warsaw, Poland.
    Dullaart, Robin P.
    Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
    Engström, Gunnar
    Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Ferrario, Marco M.
    Research Center in Epidemiology and Preventive Medicine, Department of Medicine and Surgery, University of Insubria, Varese, Italy.
    Ferrières, Jean
    Department of Cardiology, Inserm UMR1295, Toulouse Rangueil University Hospital, Toulouse, France.
    De Gaetano, Giovanni
    Department of Epidemiology and Prevention, Irccs Neuromed, Pozzilli, Italy.
    Goldbourt, Uri
    Department of Epidemiology, Tel Aviv University School of Public Health, Tel Aviv, Israel.
    Gonzalez, Clicerio
    Centro de Estudios en Diabetes, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Publica, Cuernavaca, Mexico.
    Grassi, Guido
    Clinica Medica, University of Milano Bicocca, Milan, Italy.
    Hodge, Allison M.
    Division of Cancer Epidemiology, Cancer Council Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Australia.
    Hveem, Kristian
    Hunt (Trøndelag Health Study) Research Center, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Trondheim, Norway.
    Iacoviello, Licia
    Research Center in Epidemiology and Preventive Medicine, Department of Medicine and Surgery, University of Insubria, Varese, Italy; Department of Epidemiology and Prevention, Irccs Neuromed, Pozzilli, Italy.
    Ikram, M. Kamran
    Department of Neurology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands; Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands.
    Irazola, Vilma
    Department of Chronic Diseases, Institute for Clinical Effectiveness and Health Policy, Buenos Aires, Argentina.
    Jobe, Modou
    Medical Research Council Unit the Gambia, London School of Hygiene and Tropical Medicine, Banjul, Gambia.
    Jousilahti, Pekka
    Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
    Kaleebu, Pontiano
    Medical Research Council Uganda Virus Research Institute, London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda.
    Kavousi, Maryam
    Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands.
    Kee, Frank
    The Centre for Public Health, Queens University Belfast, Belfast, United Kingdom.
    Khalili, Davood
    Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Iran.
    Koenig, Wolfgang
    Dzhk Partner Site Munich Heart Alliance, Technical University of Munich, Munich, Germany; German Heart Center, Technical University of Munich, Munich, Germany; Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany; Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
    Kontsevaya, Anna
    National Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Moscow, Russian Federation.
    Kuulasmaa, Kari
    Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
    Lackner, Karl J.
    Institute of Clinical Chemistry and Laboratory Medicine, Germany; University Medical Center of the Johannes Gutenberg University Mainz, Dzhk Partner Site Rhine Main, Mainz, Germany.
    Leistner, David M.
    University Heart and Vascular Center Frankfurt, Dzhk Partner Site Rhine Main, Frankfurt, Germany.
    Lind, Lars
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Linneberg, Allan
    Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen, Denmark; Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
    Lorenz, Thiess
    Center for Population Health Innovation, University Heart and Vascular Center Hamburg, Germany; University Medical Center Hamburg Eppendorf, Germany; German Center for Cardiovascular Research (DZHK) Partner Site Hamburg Kiel Lübeck, Germany.
    Lyngbakken, Magnus Nakrem
    Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway; K.G. Jebsen Center for Cardiac Biomarkers, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Malekzadeh, Reza
    Liver and Pancreaticobiliary Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Digestive Oncology Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
    Malyutina, Sofia
    Research Institute of Internal and Preventive Medicine, Branch of the Federal Research Center Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russian Federation.
    Mathiesen, Ellisiv B.
    Department of Clinical Medicine, University of Tromsø the Arctic University of Norway, Tromsø, Norway.
    Melander, Olle
    Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Metspalu, Andres
    Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
    Miranda, J. Jaime
    Cronicas Center of Excellence in Chronic Diseases, Universidad Peruana Cayetano Heredia, Lima, Peru; Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Australia.
    Moitry, Marie
    Department of Public Health, Strasbourg University Hospital, University of Strasbourg, Strasbourg, France.
    Mugisha, Joseph
    Medical Research Council Uganda Virus Research Institute, London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda.
    Nalini, Mahdi
    Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States; Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
    Nambi, Vijay
    Michael E. DeBakey Veterans Affairs Hospital, Baylor College of Medicine, TX, Houston, United States.
    Ninomiya, Toshiharu
    Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
    Oppermann, Karen
    School of Medicine, University of Passo Fundo, Passo Fundo, Brazil.
    D'Orsi, Eleonora
    Department of Public Health, Postgraduate Program in Public Health, Federal University of Santa Catarina, Florianopolis, Brazil.
    Pająk, Andrzej
    Department of Epidemiology and Population Studies, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland.
    Palmieri, Luigi
    Department of Cardiovascular and Endocrine Metabolic Diseases and Aging, Istituto Superiore di Sanità, Rome, Italy.
    Panagiotakos, Demosthenes
    School of Health Sciences and Education, Harokopio University, Athens, Greece.
    Perianayagam, Arokiasamy
    National Council of Applied Economic Research, Delhi, India; International Institute for Population Sciences, Mumbai, India.
    Peters, Annette
    Dzhk Partner Site Munich Heart Alliance, Technical University of Munich, Munich, Germany; Institute for Medical Information Processing, Biometry, and Epidemiology, Medical Faculty, Ludwig Maximilians Universität München, Munich, Germany; German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD) Partner Site Munich Neuherberg, Neuherberg, Germany.
    Poustchi, Hossein
    Digestive Oncology Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
    Prentice, Andrew M.
    Medical Research Council Unit the Gambia, London School of Hygiene and Tropical Medicine, Banjul, Gambia.
    Prescott, Eva
    Department of Cardiology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
    Risérus, Ulf
    Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Sweden.
    Salomaa, Veikko
    Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
    Sans, Susana
    Catalan Department of Health, Barcelona, Spain.
    Sakata, Satoko
    Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
    Schöttker, Ben
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, and Network Aging Research, Heidelberg University, Heidelberg, Germany.
    Schutte, Aletta E.
    George Institute for Global Health, Sydney, Australia; School of Population Health, Kensington, Australia; Hypertension in Africa Research Team, South African Medical Research Council Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa.
    Sepanlou, Sadaf G.
    Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
    Sharma, Sanjib Kumar
    Department of Internal Medicine, B.P. Koirala Institute of Health Sciences, Dharan, Nepal.
    Shaw, Jonathan E.
    Baker Heart and Diabetes Institute, Melbourne, Australia.
    Simons, Leon A.
    University of New South Wales, Kensington, Australia.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Tamosiunas, Abdonas
    Laboratory of Population Studies, Institute of Cardiology, Department of Preventive Medicine, Faculty of Public Health, Lithuanian University of Health Sciences, Kaunas, Lithuania.
    Thorand, Barbara
    Institute for Medical Information Processing, Biometry, and Epidemiology, Medical Faculty, Ludwig Maximilians Universität München, Munich, Germany; German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD) Partner Site Munich Neuherberg, Neuherberg, Germany.
    Tunstall-Pedoe, Hugh
    Cardiovascular Epidemiology Unit, Institute of Cardiovascular Research, University of Dundee, Dundee, United Kingdom.
    Twerenbold, Raphael
    Center for Population Health Innovation, University Heart and Vascular Center Hamburg, Germany; University Medical Center Hamburg Eppendorf, Germany; German Center for Cardiovascular Research (DZHK) Partner Site Hamburg Kiel Lübeck, Germany.
    Vanuzzo, Diego
    Monica (Monitoring Cardiovascular Diseases) Friuli Study Group, Udine, Italy.
    Veronesi, Giovanni
    Research Center in Epidemiology and Preventive Medicine, Department of Medicine and Surgery, University of Insubria, Varese, Italy.
    Waibel, Julia
    Center for Population Health Innovation, University Heart and Vascular Center Hamburg, Germany; University Medical Center Hamburg Eppendorf, Germany; German Center for Cardiovascular Research (DZHK) Partner Site Hamburg Kiel Lübeck, Germany.
    Wannamethee, S. Goya
    Research Department of Primary Care and Population Health, University College London, London, United Kingdom.
    Watanabe, Masafumi
    Global Center of Excellence Program Study Group, Yamagata University School of Medicine, Yamagata, Japan.
    Wild, Philipp S.
    Preventive Cardiology and Preventive Medicine, Mainz, Germany; Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, Mainz, Germany; University Medical Center of the Johannes Gutenberg University Mainz, Dzhk Partner Site Rhine Main, Mainz, Germany; Institute for Molecular Biology, Mainz, Germany.
    Yao, Yao
    China Center for Health Development Studies, National School of Development, Peking University, China; Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing, China.
    Zeng, Yi
    Center for Healthy Aging and Development Studies, National School of Development, Peking University, China; Center for the Study of Aging and Human Development and Geriatrics Division, Medical School of Duke University, NC, Durham, United States.
    Ziegler, Andreas
    Center for Population Health Innovation, University Heart and Vascular Center Hamburg, Germany; University Medical Center Hamburg Eppendorf, Germany; School of Mathematics, Statistics, and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa; Cardio-CARE, Davos, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
    Blankenberg, Stefan
    Center for Population Health Innovation, University Heart and Vascular Center Hamburg, Germany; University Medical Center Hamburg Eppendorf, Germany; German Center for Cardiovascular Research (DZHK) Partner Site Hamburg Kiel Lübeck, Germany; Cardio-CARE, Davos, Switzerland.
    Global effect of modifiable risk factors on cardiovascular disease and mortality2023In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 389, no 14, p. 1273-1285Article in journal (Refereed)
    Abstract [en]

    Background: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking.

    Methods: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality.

    Results: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6).

    Conclusions: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.)

  • 23. McMurray, John J
    et al.
    Holman, Rury R
    Haffner, Steven M
    Bethel, M Angelyn
    Holzhauer, Björn
    Hua, Tsushung A
    Belenkov, Yuri
    Boolell, Mitradev
    Buse, John B
    Buckley, Brendan M
    Chacra, Antonio R
    Chiang, Fu-Tien
    Charbonnel, Bernard
    Chow, Chun-Chung
    Davies, Melanie J
    Deedwania, Prakash
    Diem, Peter
    Einhorn, Daniel
    Fonseca, Vivian
    Fulcher, Gregory R
    Gaciong, Zbigniew
    Gaztambide, Sonia
    Giles, Thomas
    Horton, Edward
    Ilkova, Hasan
    Jenssen, Trond
    Kahn, Steven E
    Krum, Henry
    Laakso, Markku
    Leiter, Lawrence A
    Levitt, Naomi S
    Mareev, Viacheslav
    Martinez, Felipe
    Masson, Chantal
    Mazzone, Theodore
    Meaney, Eduardo
    Nesto, Richard
    Pan, Changyu
    Prager, Rudolf
    Raptis, Sotirios A
    Rutten, Guy E H M
    Sandström, Herbert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Schaper, Frank
    Scheen, Andre
    Schmitz, Ole
    Sinay, Isaac
    Soska, Vladimir
    Stender, Steen
    Tamás, Gyula
    Tognoni, Gianni
    Tuomilehto, Jaako
    Villamil, Alberto S
    Vozár, Juraj
    Califf, Robert M
    Effect of valsartan on the incidence of diabetes and cardiovascular events2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 362, no 16, p. 1477-1490Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance.

    METHODS: In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization.

    RESULTS: The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85).

    CONCLUSIONS: Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

  • 24. Miller, Timothy
    et al.
    Cudkowicz, Merit
    Shaw, Pamela J.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Atassi, Nazem
    Bucelli, Robert C.
    Genge, Angela
    Glass, Jonathan
    Ladha, Shafeeq
    Ludolph, Albert L.
    Maragakis, Nicholas J.
    McDermott, Christopher J.
    Pestronk, Alan
    Ravits, John
    Salachas, Francois
    Trudell, Randall
    Van Damme, Philip
    Zinman, Lorne
    Bennett, C. Frank
    Lane, Roger
    Sandrock, Alfred
    Runz, Heiko
    Graham, Danielle
    Houshyar, Hani
    McCampbell, Alexander
    Nestorov, Ivan
    Chang, Ih
    McNeill, Manjit
    Fanning, Laura
    Fradette, Stephanie
    Ferguson, Toby A.
    Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS2020In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 383, no 2, p. 109-119Article in journal (Refereed)
    Abstract [en]

    Background: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.

    Methods: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured.

    Results: A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose.

    Conclusions: In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.)

    In a phase 1-2 dose-escalation trial involving adults with ALS due to SOD1 mutations who received intrathecal tofersen (an antisense oligonucleotide) or placebo, the levels of mutant SOD1 in the CSF were 33 percentage points lower in the highest-dose tofersen group than in the placebo group.

  • 25. Mills, Nicholas L
    et al.
    Törnqvist, Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Gonzalez, Manuel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Vink, Elen
    Robinson, Simon D
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Boon, Nicholas A
    Donaldson, Ken
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Newby, David E
    Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease2007In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 357, no 11, p. 1075-1082Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Exposure to air pollution from traffic is associated with adverse cardiovascular events. The mechanisms for this association are unknown. We conducted a controlled exposure to dilute diesel exhaust in patients with stable coronary heart disease to determine the direct effect of air pollution on myocardial, vascular, and fibrinolytic function.

    METHODS: In a double-blind, randomized, crossover study, 20 men with prior myocardial infarction were exposed, in two separate sessions, to dilute diesel exhaust (300 mug per cubic meter) or filtered air for 1 hour during periods of rest and moderate exercise in a controlled-exposure facility. During the exposure, myocardial ischemia was quantified by ST-segment analysis using continuous 12-lead electrocardiography. Six hours after exposure, vasomotor and fibrinolytic function were assessed by means of intraarterial agonist infusions.

    RESULTS: During both exposure sessions, the heart rate increased with exercise (P<0.001); the increase was similar during exposure to diesel exhaust and exposure to filtered air (P=0.67). Exercise-induced ST-segment depression was present in all patients, but there was a greater increase in the ischemic burden during exposure to diesel exhaust (-22+/-4 vs. -8+/-6 millivolt seconds, P<0.001). Exposure to diesel exhaust did not aggravate preexisting vasomotor dysfunction, but it did reduce the acute release of endothelial tissue plasminogen activator (P=0.009; 35% decrease in the area under the curve).

    CONCLUSIONS: Brief exposure to dilute diesel exhaust promotes myocardial ischemia and inhibits endogenous fibrinolytic capacity in men with stable coronary heart disease. Our findings point to ischemic and thrombotic mechanisms that may explain in part the observation that exposure to combustion-derived air pollution is associated with adverse cardiovascular events.

  • 26. Naucler, Pontus
    et al.
    Ryd, Walter
    Törnberg, Sven
    Strand, Anders
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elfgren, Kristina
    Rådberg, Thomas
    Strander, Björn
    Johansson, Bo
    Forslund, Ola
    Hansson, Bengt-Göran
    Rylander, Eva
    Dillner, Joakim
    Human papillomavirus and Papanicolaou tests to screen for cervical cancer2007In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 357, no 16, p. 1589-1597Article in journal (Refereed)
    Abstract [en]

    Background: Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown.

    Methods: In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group. Comprehensive registry data were used to follow the women for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated.

    Results: At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions. At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy.

    Conclusions: The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations.

  • 27. Nelson, C. P.
    et al.
    Hamby, S. E.
    Saleheen, D.
    Hopewell, J. C.
    Zeng, L.
    Assimes, T. L.
    Kanoni, S.
    Willenborg, C.
    Burgess, S.
    Amouyel, P.
    Anand, S.
    Blankenberg, S.
    Boehm, B. O.
    Clarke, R. J.
    Collins, R.
    Dedoussis, G.
    Farrall, M.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Lund University Diabetes Center, Skåne University Hospital; Department of Nutrition, Harvard School of Public Health, USA.
    Groop, L.
    Hall, A. S.
    Hamsten, A.
    Hengstenberg, C.
    Hovingh, G. Kees
    Ingelsson, E.
    Kathiresan, S.
    Kee, F.
    Koenig, I. R.
    Kooner, J.
    Lehtimaeki, T.
    Maerz, W.
    McPherson, R.
    Metspalu, A.
    Nieminen, M. S.
    O'Donnell, C. J.
    Palmer, C. N. A.
    Peters, A.
    Perola, M.
    Reilly, M. P.
    Ripatti, S.
    Roberts, R.
    Salomaa, V.
    Shah, S. H.
    Schreiber, S.
    Siegbahn, A.
    Thorsteinsdottir, U.
    Veronesi, G.
    Wareham, N.
    Willer, C. J.
    Zalloua, P. A.
    Erdmann, J.
    Deloukas, P.
    Watkins, H.
    Schunkert, H.
    Danesh, J.
    Thompson, J. R.
    Samani, N. J.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Genetically Determined Height and Coronary Artery Disease2015In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 372, no 17, p. 1608-1618Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear.

    METHODS We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes.

    RESULTS We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quar-tile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis.

    CONCLUSIONS There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association.

  • 28. Neumann, J. T.
    et al.
    Twerenbold, R.
    Ojeda, F.
    Soerensen, N. A.
    Chapman, A. R.
    Shah, A. S. V.
    Anand, A.
    Boeddinghaus, J.
    Nestelberger, T.
    Badertscher, P.
    Mokhtari, A.
    Pickering, J. W.
    Troughton, R. W.
    Greenslade, J.
    Parsonage, W.
    Mueller-Hennessen, M.
    Gori, T.
    Jernberg, T.
    Morris, N.
    Liebetrau, C.
    Hamm, C.
    Katus, H. A.
    Muenzel, T.
    Landmesser, U.
    Salomaa, V.
    Iacoviello, L.
    Ferrario, M. M.
    Giampaoli, S.
    Kee, F.
    Thorand, B.
    Peters, A.
    Borchini, R.
    Jorgensen, T.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Sans, S.
    Tunstall-Pedoe, H.
    Kuulasmaa, K.
    Renne, T.
    Lackner, K. J.
    Worster, A.
    Body, R.
    Ekelund, U.
    Kavsak, P. A.
    Keller, T.
    Lindahl, B.
    Wild, P.
    Giannitsis, E.
    Than, M.
    Cullen, L. A.
    Mills, N. L.
    Mueller, C.
    Zeller, T.
    Westermann, D.
    Blankenberg, S.
    Application of High-Sensitivity Troponin in Suspected Myocardial Infarction2019In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 380, no 26, p. 2529-2540Article in journal (Refereed)
    Abstract [en]

    BackgroundData regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes. MethodsIn 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation-validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days. ResultsAmong 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set. ConclusionsA risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes.

  • 29. Nordanstig, Joakim
    et al.
    James, Stefan
    Andersson, Manne
    Andersson, Mattias
    Danielsson, Peter
    Gillgren, Peter
    Delle, Martin
    Engström, Jan
    Fransson, Torbjörn
    Hamoud, Maher
    Hilbertson, Anna
    Johansson, Patrik
    Karlsson, Lars
    Kragsterman, Björn
    Lindgren, Hans
    Ludwigs, Karin
    Mellander, Stefan
    Nyman, Niklas
    Renlund, Henrik
    Sigvant, Birgitta
    Skoog, Per
    Starck, Joachim
    Tegler, Gustaf
    Toivola, Asko
    Truedson, Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Wahlgren, Carl-Magnus
    Wallinder, Jonas
    Öjersjö, Andreas
    Falkenberg, Mårten
    Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease2020In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 383, no 26, p. 2538-2546Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The results of a recent meta-analysis aroused concern about an increased risk of death associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral artery disease.

    METHODS: We conducted an unplanned interim analysis of data from a multicenter, randomized, open-label, registry-based clinical trial. At the time of the analysis, 2289 patients had been randomly assigned to treatment with drug-coated devices (the drug-coated–device group, 1149 patients) or treatment with uncoated devices (the uncoated-device group, 1140 patients). Randomization was stratified according to disease severity on the basis of whether patients had chronic limb-threatening ischemia (1480 patients) or intermittent claudication (809 patients). The single end point for this interim analysis was all-cause mortality.

    RESULTS: No patients were lost to follow-up. Paclitaxel was used as the coating agent for all the drug-coated devices. During a mean follow-up of 2.49 years, 574 patients died, including 293 patients (25.5%) in the drug-coated–device group and 281 patients (24.6%) in the uncoated-device group (hazard ratio, 1.06; 95% confidence interval, 0.92 to 1.22). At 1 year, all-cause mortality was 10.2% (117 patients) in the drug-coated–device group and 9.9% (113 patients) in the uncoated-device group. During the entire follow-up period, there was no significant difference in the incidence of death between the treatment groups among patients with chronic limb-threatening ischemia (33.4% [249 patients] in the drug-coated–device group and 33.1% [243 patients] in the uncoated-device group) or among those with intermittent claudication (10.9% [44 patients] and 9.4% [38 patients], respectively).

    CONCLUSIONS: In this randomized trial in which patients with peripheral artery disease received treatment with paclitaxel-coated or uncoated endovascular devices, the results of an unplanned interim analysis of all-cause mortality did not show a difference between the groups in the incidence of death during 1 to 4 years of follow-up.

  • 30.
    Normark, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Vikström, Linnea
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Yong-Dae, Gwon
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Persson, Ida-Lisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Edin, Alicia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Björsell, Tove
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Dernstedt, Andy
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Christ, Wanda
    Tevell, Staffan
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Klingström, Jonas
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Heterologous ChAdOx1 nCoV-19 and mRNA-1273 Vaccination2021In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 385, no 11, p. 1049-1051Article in journal (Refereed)
  • 31. Parker, C.
    et al.
    Nilsson, S.
    Heinrich, D.
    Helle, S. I.
    O'Sullivan, J. M.
    Fossa, S. D.
    Chodacki, A.
    Wiechno, P.
    Logue, J.
    Seke, M.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johannessen, D. C.
    Hoskin, P.
    Bottomley, D.
    James, N. D.
    Solberg, A.
    Syndikus, I.
    Kliment, J.
    Wedel, S.
    Boehmer, S.
    Dall'Oglio, M.
    Franzen, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Coleman, R.
    Vogelzang, N. J.
    O'Bryan-Tear, C. G.
    Staudacher, K.
    Garcia-Vargas, J.
    Shan, M.
    Bruland, O. S.
    Sartor, O.
    Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer2013In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 369, no 3, p. 213-223Article in journal (Refereed)
    Abstract [en]

    Background Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. Methods In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. Results At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. Conclusions In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.)

  • 32. Ravaud, Alain
    et al.
    Motzer, Robert J
    Pandha, Hardev S
    George, Daniel J
    Pantuck, Allan J
    Patel, Anup
    Chang, Yen-Hwa
    Escudier, Bernard
    Donskov, Frede
    Magheli, Ahmed
    Carteni, Giacomo
    Laguerre, Brigitte
    Tomczak, Piotr
    Breza, Jan
    Gerletti, Paola
    Lechuga, Mariajose
    Lin, Xun
    Martini, Jean-Francois
    Ramaswamy, Krishnan
    Casey, Michelle
    Staehler, Michael
    Patard, Jean-Jacques
    Ljungberg, Börje
    Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.2016In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 375, no 23, p. 2246-2254Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy.

    METHODS: In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety.

    RESULTS: The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects.

    CONCLUSIONS: Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).

  • 33.
    Semenza, Jan C.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health. Heidelberg Institute of Global Health, University of Heidelberg, Heidelberg, Germany.
    Ko, Albert I.
    Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT; Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil.
    Waterborne diseases that are sensitive to climate variability and climate change2023In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 389, no 23, p. 2175-2187Article, review/survey (Refereed)
  • 34. Sternberg, Cora N.
    et al.
    Fizazi, Karim
    Saad, Fred
    Shore, Neal D.
    De Giorgi, Ugo
    Penson, David F.
    Ferreira, Ubirajara
    Efstathiou, Eleni
    Madziarska, Katarzyna
    Kolinsky, Michael P.
    Cubero, Daniel I. G.
    Noerby, Bettina
    Zohren, Fabian
    Lin, Xun
    Modelska, Katharina
    Sugg, Jennifer
    Steinberg, Joyce
    Hussain, Maha
    Ljungberg, Börje (Contributor)
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer2020In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 382, no 23, p. 2197-2206Article in journal (Refereed)
    Abstract [en]

    Background: Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported.

    Methods: In this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O’Brien–Fleming–type alpha-spending function.

    Results: As of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval [CI], 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P=0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events.

    Conclusions: Enzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.)

  • 35. Stitziel, Nathan O.
    et al.
    Stirrups, Kathleen E.
    Masca, Nicholas G. D.
    Erdmann, Jeanette
    Ferrario, Paola G.
    Koenig, Inke R.
    Weeke, Peter E.
    Webb, Thomas R.
    Auer, Paul L.
    Schick, Ursula M.
    Lu, Yingchang
    Zhang, He
    Dube, Marie-Pierre
    Goel, Anuj
    Farrall, Martin
    Peloso, Gina M.
    Won, Hong-Hee
    Do, Ron
    van Iperen, Erik
    Kanoni, Stavroula
    Kruppa, Jochen
    Mahajan, Anubha
    Scott, Robert A.
    Willenborg, Christina
    Braund, Peter S.
    van Capelleveen, Julian C.
    Doney, Alex S. F.
    Donnelly, Louise A.
    Asselta, Rosanna
    Merlini, Piera A.
    Duga, Stefano
    Marziliano, Nicola
    Denny, Josh C.
    Shaffer, Christian M.
    El-Mokhtari, Nour Eddine
    Franke, Andre
    Gottesman, Omri
    Heilmann, Stefanie
    Hengstenberg, Christian
    Hoffmann, Per
    Holmen, Oddgeir L.
    Hveem, Kristian
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Joeckel, Karl-Heinz
    Kessler, Thorsten
    Kriebel, Jennifer
    Laugwitz, Karl L.
    Marouli, Eirini
    Martinelli, Nicola
    McCarthy, Mark I.
    Van Zuydam, Natalie R.
    Meisinger, Christa
    Esko, Tonu
    Mihailov, Evelin
    Andersson Escher, Stefan
    Alver, Maris
    Moebus, Susanne
    Morris, Andrew D.
    Mueller-Nurasyid, Martina
    Nikpay, Majid
    Olivieri, Oliviero
    Perreault, Louis-Philippe Lemieux
    AlQarawi, Alaa
    Robertson, Neil R.
    Akinsanya, Karen O.
    Reilly, Dermot F.
    Vogt, Thomas F.
    Yin, Wu
    Asselbergs, Folkert W.
    Kooperberg, Charles
    Jackson, Rebecca D.
    Stahl, Eli
    Strauch, Konstantin
    Varga, Tibor V.
    Waldenberger, Melanie
    Zeng, Lingyao
    Kraja, Aldi T.
    Liu, Chunyu
    Ehret, Georg B.
    Newton-Cheh, Christopher
    Chasman, Daniel I.
    Chowdhury, Rajiv
    Ferrario, Marco
    Ford, Ian
    Jukema, J. Wouter
    Kee, Frank
    Kuulasmaa, Kari
    Nordestgaard, Borge G.
    Perola, Markus
    Saleheen, Danish
    Sattar, Naveed
    Surendran, Praveen
    Tregouet, David
    Young, Robin
    Howson, Joanna M. M.
    Butterworth, Adam S.
    Danesh, John
    Ardissino, Diego
    Bottinger, Erwin P.
    Erbel, Raimund
    Franks, Paul W.
    Harvard University; Umeå University Hospital; Lund University.
    Girelli, Domenico
    Hall, Alistair S.
    Hovingh, G. Kees
    Kastrati, Adnan
    Lieb, Wolfgang
    Meitinger, Thomas
    Kraus, William E.
    Shah, Svati H.
    McPherson, Ruth
    Orho-Melander, Marju
    Melander, Olle
    Metspalu, Andres
    Palmer, Colin N. A.
    Peters, Annette
    Rader, Daniel J.
    Reilly, Muredach P.
    Loos, Ruth J. F.
    Reiner, Alex P.
    Roden, Dan M.
    Tardif, Jean-Claude
    Thompson, John R.
    Wareham, Nicholas J.
    Watkins, Hugh
    Willer, Cristen J.
    Kathiresan, Sekar
    Deloukas, Panos
    Samani, Nilesh J.
    Schunkert, Heribert
    Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease2016In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 374, no 12, p. 1134-1144Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.

  • 36. Vriezinga, S. L.
    et al.
    Auricchio, R.
    Bravi, E.
    Castillejo, G.
    Chmielewska, A.
    Crespo Escobar, P.
    Kolaček, S.
    Koletzko, S.
    Korponay-Szabo, I. R.
    Mummert, E.
    Polanco, I.
    Putter, H.
    Ribes-Koninckx, C.
    Shamir, R.
    Szajewska, H.
    Werkstetter, K.
    Greco, L.
    Gyimesi, J.
    Hartman, C.
    Esch, C. Hogen
    Hopman, E.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Koltai, T.
    Koning, F.
    Martinez-Ojinaga, E.
    te Marvelde, C.
    Pavic, A. Mocic
    Romanos, J.
    Stoopman, E.
    Villanacci, V.
    Wijmenga, C.
    Troncone, R.
    Mearin, M. L.
    Randomized feeding intervention in infants at high risk for celiac disease2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 14, p. 1304-1315Article in journal (Refereed)
    Abstract [en]

    BACKGROUND A window of opportunity has been suggested for reducing the risk of celiac disease by introducing gluten to infants at 4 to 6 months of age. METHODS We performed a multicenter, randomized, double-blind, placebo-controlled dietary-intervention study involving 944 children who were positive for HLA-DQ2 or HLA-DQ8 and had at least one first-degree relative with celiac disease. From 16 to 24 weeks of age, 475 participants received 100 mg of immunologically active gluten daily, and 469 received placebo. Anti-transglutaminase type 2 and antigliadin antibodies were periodically measured. The primary outcome was the frequency of biopsy-confirmed celiac disease at 3 years of age. RESULTS Celiac disease was confirmed by means of biopsies in 77 children. To avoid underestimation of the frequency of celiac disease, 3 additional children who received a diagnosis of celiac disease according to the 2012 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition diagnostic criteria (without having undergone biopsies) were included in the analyses (80 children; median age, 2.8 years; 59% were girls). The cumulative incidence of celiac disease among patients 3 years of age was 5.2% (95% confidence interval [CI], 3.6 to 6.8), with similar rates in the gluten group and the placebo group (5.9% [95% CI, 3.7 to 8.1] and 4.5% [95% CI, 2.5 to 6.5], respectively; hazard ratio in the gluten group, 1.23; 95% CI, 0.79 to 1.91). Rates of elevated levels of anti-transglutaminase type 2 and antigliadin antibodies were also similar in the two study groups (7.0% [95% CI, 4.7 to 9.4] in the gluten group and 5.7% [95% CI, 3.5 to 7.9] in the placebo group; hazard ratio, 1.14; 95% CI, 0.76 to 1.73). Breast-feeding, regardless of whether it was exclusive or whether it was ongoing during gluten introduction, did not significantly influence the development of celiac disease or the effect of the intervention. CONCLUSIONS As compared with placebo, the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age in this group of high-risk children. (Funded by the European Commission and others; PreventCD Current Controlled Trials number, ISRCTN74582487.)

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