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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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis2018Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, nr 1, s. 11-21Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    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 Years2017Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, nr 1, s. 13-27Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Hempel, Maja
    Santer, René
    Nordström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Tsiakas, Konstantinos
    Johannsen, Jessika
    Volk, Alexander E.
    Bierhals, Tatjana
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Phenotype in an Infant with SOD1 Homozygous Truncating Mutation2019Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, nr 5, s. 486-488Artikel i tidskrift (Refereegranskat)
  • 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.2014Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, nr 5Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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 glioblastoma2014Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, nr 8, s. 709-722Artikel i tidskrift (Refereegranskat)
    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. 

  • 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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. 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 Disease2014Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, nr 1, s. 22-31Artikel i tidskrift (Refereegranskat)
    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 sumatriptan1991Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, nr 325, s. 322-326Artikel i tidskrift (Refereegranskat)
  • 8. Erlinge, D.
    et al.
    Omerovic, E.
    Frobert, O.
    Linder, Robert
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    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, A.
    Bhiladvala, P.
    Lindvall, B.
    Lundin, A.
    Tödt, T.
    Ioanes, D.
    Råmunddal, T.
    Kellerth, T.
    Zagozdzon, L.
    Götberg, M.
    Andersson, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Angerås, O.
    Östlund, O.
    Lagerqvist, B.
    Held, C.
    Wallentin, L.
    Scherstén, F.
    Eriksson, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Koul, S.
    James, S.
    Bivalirudin versus heparin monotherapy in myocardial infarction2017Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, nr 12, s. 1132-1142Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Childhood obesity, other cardiovascular risk factors, and premature death2010Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 362, nr 13, s. 1840-1842Artikel, recension (Övrigt vetenskapligt)
  • 10.
    Franks, Paul W
    et al.
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Medicin.
    Hanson, Robert L
    Knowler, William C
    Sievers, Maurice L
    Bennett, Peter H
    Looker, Helen C
    Childhood obesity, other cardiovascular risk factors, and premature death.2010Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 362, nr 6, s. 485-493Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi. Heart Centrum.
    Robertson, Lotta
    Sandhall, Lennart
    Sjogren, Iwar
    Ostlund, Ollie
    Harnek, Jan
    James, Stefan K.
    Thrombus Aspiration during ST-Segment Elevation Myocardial Infarction2013Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 369, nr 17, s. 1587-1597Artikel i tidskrift (Refereegranskat)
    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.
    Hallberg, Bengt
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Palmer, Ruth H
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Crizotinib: latest champion in the cancer wars?2010Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 363, nr 18, s. 1760-1762Artikel i tidskrift (Refereegranskat)
  • 13. 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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    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 Events2010Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 362, nr 16, s. 1463-1476Artikel i tidskrift (Refereegranskat)
    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.)

  • 14. 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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    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.2008Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 358, nr 9, s. 900-909Artikel i tidskrift (Refereegranskat)
    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).

  • 15. 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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    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 Prediction2012Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, nr 14, s. 1310-1320Artikel i tidskrift (Refereegranskat)
    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.)

  • 16. 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 Infarction2014Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, nr 12, s. 1111-1120Artikel i tidskrift (Refereegranskat)
    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.

  • 17. 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.2012Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, nr 21, s. 2006-14Artikel i tidskrift (Refereegranskat)
    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.).

  • 18. 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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för hållbar hälsa.
    Åström, Christofer
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för hållbar hälsa.
    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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för hållbar hälsa. 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 Cities2019Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, nr 8, s. 705-715Artikel i tidskrift (Refereegranskat)
    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.).

  • 19.
    Löfgren, Jenny
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Nordin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    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 Repair2016Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 374, nr 2, s. 146-153Artikel i tidskrift (Refereegranskat)
    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.

  • 20. 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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    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 events2010Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 362, nr 16, s. 1477-1490Artikel i tidskrift (Refereegranskat)
    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.)

  • 21. Mills, Nicholas L
    et al.
    Törnqvist, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Gonzalez, Manuel
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Vink, Elen
    Robinson, Simon D
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Boon, Nicholas A
    Donaldson, Ken
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Newby, David E
    Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease2007Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 357, nr 11, s. 1075-1082Artikel i tidskrift (Refereegranskat)
    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.

  • 22. Naucler, Pontus
    et al.
    Ryd, Walter
    Törnberg, Sven
    Strand, Anders
    Wadell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    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 cancer2007Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 357, nr 16, s. 1589-1597Artikel i tidskrift (Refereegranskat)
    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.

  • 23. 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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. 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 universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Genetically Determined Height and Coronary Artery Disease2015Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 372, nr 17, s. 1608-1618Artikel i tidskrift (Refereegranskat)
    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.

  • 24. 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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    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 Infarction2019Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 380, nr 26, s. 2529-2540Artikel i tidskrift (Refereegranskat)
    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.

  • 25. 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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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 Cancer2013Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 369, nr 3, s. 213-223Artikel i tidskrift (Refereegranskat)
    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.)

  • 26. 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.2016Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 375, nr 23, s. 2246-2254Artikel i tidskrift (Refereegranskat)
    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 .).

  • 27. 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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    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 Disease2016Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 374, nr 12, s. 1134-1144Artikel i tidskrift (Refereegranskat)
    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.

  • 28. 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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    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 disease2014Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, nr 14, s. 1304-1315Artikel i tidskrift (Refereegranskat)
    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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