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  • 51. Holman, Rury R
    et al.
    Bethel, M Angelyn
    Mentz, Robert J
    Thompson, Vivian P
    Lokhnygina, Yuliya
    Buse, John B
    Chan, Juliana C
    Choi, Jasmine
    Gustavson, Stephanie M
    Iqbal, Nayyar
    Maggioni, Aldo P
    Marso, Steven P
    Öhman, Peter
    Pagidipati, Neha J
    Poulter, Neil
    Ramachandran, Ambady
    Zinman, Bernard
    Hernandez, Adrian F
    Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.2017Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, nr 13, s. 1228-1239Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.

    METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.

    RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups.

    CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .).

  • 52.
    Holmberg, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Bill-Axelson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Helgesen, Fred
    Salo, Jaakko O.
    Folmerz, Per
    Häggman, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Andersson, Swen-Olof
    Spångberg, Anders
    Busch, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nordling, Steg
    Palmgren, Juni
    Adami, Hans-Olov
    Johansson, Jan-Erik
    Norlén, Bo Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer2002Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 347, nr 11, s. 781-789Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Radical prostatectomy is widely used in the treatment of early prostate cancer. The possible survival benefit of this treatment, however, is unclear. We conducted a randomized trial to address this question. METHODS: From October 1989 through February 1999, 695 men with newly diagnosed prostate cancer in International Union against Cancer clinical stage T1b, T1c, or T2 were randomly assigned to watchful waiting or radical prostatectomy. We achieved complete follow-up through the year 2000 with blinded evaluation of causes of death. The primary end point was death due to prostate cancer, and the secondary end points were overall mortality, metastasis-free survival, and local progression. RESULTS: During a median of 6.2 years of follow-up, 62 men in the watchful-waiting group and 53 in the radical-prostatectomy group died (P=0.31). Death due to prostate cancer occurred in 31 of 348 of those assigned to watchful waiting (8.9 percent) and in 16 of 347 of those assigned to radical prostatectomy (4.6 percent) (relative hazard, 0.50; 95 percent confidence interval, 0.27 to 0.91; P=0.02). Death due to other causes occurred in 31 of 348 men in the watchful-waiting group (8.9 percent) and in 37 of 347 men in the radical-prostatectomy group (10.6 percent). The men assigned to surgery had a lower relative risk of distant metastases than the men assigned to watchful waiting (relative hazard, 0.63; 95 percent confidence interval, 0.41 to 0.96). CONCLUSIONS: In this randomized trial, radical prostatectomy significantly reduced disease-specific mortality, but there was no significant difference between surgery and watchful waiting in terms of overall survival.

  • 53. Hom, Geoffrey
    et al.
    Graham, Robert R
    Modrek, Barmak
    Taylor, Kimberly E
    Ortmann, Ward
    Garnier, Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    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
    Petri, Michelle
    Manzi, Susan
    Seldin, Michael F
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Criswell, Lindsey A
    Gregersen, Peter K
    Behrens, Timothy W
    Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX2008Ingår 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 STAT4 are 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).

    CONCLUSIONS:

    We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.

  • 54.
    James, Stefan K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Stenestrand, Ulf
    Lindbäck, Johan
    Carlsson, Jörg
    Scherstén, Fredrik
    Nilsson, Tage
    Wallentin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Lagerqvist, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Long-term safety and efficacy of drug-eluting versus bare-metal stents in Sweden2009Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 360, nr 19, s. 1933-1945Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The long-term safety and efficacy of drug-eluting coronary stents have been questioned. METHODS: We evaluated 47,967 patients in Sweden who received a coronary stent and were entered into the Swedish Coronary Angiography and Angioplasty Registry between 2003 and 2006 and for whom complete follow-up data were available for 1 to 5 years (mean, 2.7). In the primary analysis, we compared patients who received one drug-eluting coronary stent (10,294 patients) with those who received one bare-metal stent (18,659), after adjustment for differences in clinical characteristics of the patients and characteristics of the vessels and lesions. RESULTS: Analyses of outcome were based on 2380 deaths and 3198 myocardial infarctions. There was no overall difference between the group that received drug-eluting stents and the group that received bare-metal stents in the combined end point of death or myocardial infarction (relative risk with drug-eluting stents, 0.96; 95% confidence interval [CI], 0.89 to 1.03) or the individual end points of death (relative risk, 0.94; 95% CI, 0.85 to 1.05) and myocardial infarction (relative risk, 0.97; 95% CI, 0.88 to 1.06), and there was no significant difference in outcome among subgroups stratified according to the indication for stent implantation. Patients who received drug-eluting stents in 2003 had a significantly higher rate of late events than patients who received bare-metal stents in the same year, but we did not observe any difference in outcome among patients treated in later years. The average rate of restenosis during the first year was 3.0 events per 100 patient-years with drug-eluting stents versus 4.7 with bare-metal stents (adjusted relative risk, 0.43; 95% CI, 0.36 to 0.52); 39 patients would need to be treated with drug-eluting stents to prevent one case of restenosis. Among high-risk patients, the adjusted risk of restenosis was 74% lower with drug-eluting stents than with bare-metal stents, and only 10 lesions would need to be treated to prevent one case of restenosis. CONCLUSIONS: As compared with bare-metal stents, drug-eluting stents are associated with a similar long-term incidence of death or myocardial infarction and provide a clinically important decrease in the rate of restenosis among high-risk patients.

  • 55.
    Johnson, Peter
    et al.
    Univ Southampton, Canc Res UK Ctr, Southampton SO16 6YD, Hants, England..
    Federico, Massimo
    Univ Modena & Reggio Emilia, Dept Diagnost Clin & Publ Hlth Med, Modena, Italy..
    Kirkwood, Amy
    Canc Res UK, London, England.;UCL, Canc Trials Ctr, London, England..
    Fossa, Alexander
    Oslo Univ Hosp, Dept Med Oncol, Oslo, Norway..
    Berkahn, Leanne
    Auckland City Hosp, Dept Haematol, Auckland, New Zealand..
    Carella, Angelo
    San Martino Univ Hosp, Dept Hematol, Genoa, Italy..
    d'Amore, Francesco
    Aarhus Univ Hosp, Dept Hematol, DK-8000 Aarhus, Denmark..
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Franceschetto, Antonella
    Univ Modena & Reggio Emilia, Dept Diagnost Clin & Publ Hlth Med, Modena, Italy..
    Fulham, Michael
    Royal Prince Alfred Hosp, Dept Mol Imaging, Sydney, NSW, Australia..
    Luminari, Stefano
    Univ Modena & Reggio Emilia, Dept Diagnost Clin & Publ Hlth Med, Modena, Italy.;IRCCS, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy..
    O'Doherty, Michael
    Kings Coll London, Kings Hlth Partners, St Thomas Hosp, PET Imaging Ctr, London WC2R 2LS, England..
    Patrick, Pip
    Canc Res UK, London, England.;UCL, Canc Trials Ctr, London, England..
    Roberts, Thomas
    Canc Res UK, London, England.;UCL, Canc Trials Ctr, London, England..
    Sidra, Gamal
    Lincoln Cty Hosp, Dept Haematol, Lincoln, England..
    Stevens, Lindsey
    Canc Res UK, London, England.;UCL, Canc Trials Ctr, London, England..
    Smith, Paul
    Canc Res UK, London, England.;UCL, Canc Trials Ctr, London, England..
    Trotman, Judith
    Univ Sydney, Concord Repatriat Gen Hosp, Sydney, NSW 2006, Australia..
    Viney, Zaid
    Kings Coll London, Kings Hlth Partners, St Thomas Hosp, PET Imaging Ctr, London WC2R 2LS, England..
    Radford, John
    Christie Hosp, Dept Med Oncol, Manchester, Lancs, England..
    Barrington, Sally
    Kings Coll London, Kings Hlth Partners, St Thomas Hosp, PET Imaging Ctr, London WC2R 2LS, England..
    Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma2016Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 374, nr 25, s. 2419-2429Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND We tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkin's lymphoma. METHODS Patients with newly diagnosed advanced classic Hodgkin's lymphoma underwent a baseline PET-CT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points. RESULTS A total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, -3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkin's lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%. CONCLUSIONS Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy.

  • 56. Jordan, Stanley C
    et al.
    Lorant, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Choi, Jua
    IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation.2017Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, nr 17, s. 1693-4Artikel i tidskrift (Refereegranskat)
  • 57.
    Jordan, Stanley C.
    et al.
    Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA..
    Lorant, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Choi, Jua
    Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA..
    Reply to: IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation2017Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, nr 17, s. 1693-1694Artikel i tidskrift (Övrigt vetenskapligt)
  • 58. Jordan, Stanley C
    et al.
    Lorant, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Choi, Jua
    Kjellman, Christian
    Winstedt, Lena
    Bengtsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Zhang, Xiaohai
    Eich, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Toyoda, Mieko
    Eriksson, Britt-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ge, Shili
    Peng, Alice
    Järnum, Sofia
    Wood, Kathryn J
    Lundgren, Torbjörn
    Wennberg, Lars
    Bäckman, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Larsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Villicana, Rafael
    Kahwaji, Joe
    Louie, Sabrina
    Kang, Alexis
    Haas, Mark
    Nast, Cynthia
    Vo, Ashley
    Tufveson, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation.2017Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, nr 5, s. 442-453Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Donor-specific antibodies create an immunologic barrier to transplantation. Current therapies to modify donor-specific antibodies are limited and ineffective in the most highly HLA-sensitized patients. The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab')2 and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization. We report on the combined experience of two independently performed open-label, phase 1-2 trials (conducted in Sweden and the United States) that assessed the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor.

    METHODS: We administered IdeS to 25 highly HLA-sensitized patients (11 patients in Uppsala or Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from an HLA-incompatible donor. Frequent monitoring for adverse events, outcomes, donor-specific antibodies, and renal function was performed, as were renal biopsies. Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids. Patients in the U.S. study also received intravenous immune globulin and rituximab after transplantation to prevent antibody rebound.

    RESULTS: Recipients in the U.S. study had a significantly longer cold ischemia time (the time elapsed between procurement of the organ and transplantation), a significantly higher rate of delayed graft function, and significantly higher levels of class I donor-specific antibodies than those in the Swedish study. A total of 38 serious adverse events occurred in 15 patients (5 events were adjudicated as being possibly related to IdeS). At transplantation, total IgG and HLA antibodies were eliminated. A total of 24 of 25 patients had perfusion of allografts after transplantation. Antibody-mediated rejection occurred in 10 patients (7 patients in the U.S. study and 3 in the Swedish study) at 2 weeks to 5 months after transplantation; all these patients had a response to treatment. One graft loss, mediated by non-HLA IgM and IgA antibodies, occurred.

    CONCLUSIONS: IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible transplantation in 24 of 25 patients. (Funded by Hansa Medical; ClinicalTrials.gov numbers, NCT02224820 , NCT02426684 , and NCT02475551 .).

  • 59. 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
    Björkelund, Cecilia
    Brenner, Hermann
    Brunner, Eric
    Clarke, Robert
    Cooper, Jackie A
    Cremer, Peter
    Cushman, Mary
    Dagenais, Gilles R
    D'Agostino, Ralph B
    Dankner, Rachel
    Davey-Smith, George
    Deeg, Dorly
    Dekker, Jacqueline M
    Engström, 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
    Jørgensen, Torben
    Kiechl, Stefan
    Kitamura, Akihiko
    Kiyohara, Yutaka
    Koenig, Wolfgang
    Kromhout, Daan
    Kuller, Lewis H
    Lawlor, Debbie A
    Meade, Tom W
    Nissinen, Aulikki
    Nordestgaard, Børge 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
    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.).

  • 60.
    Kempen, Thomas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Correspondence: A Trial of Blood-Pressure Reduction in Black Barbershops2018Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, nr 2, s. 199-199Artikel i tidskrift (Övrigt vetenskapligt)
  • 61. Klein, T. E.
    et al.
    Altman, R. B.
    Eriksson, Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Gage, B. F.
    Kimmel, S. E.
    Lee, M-T. M.
    Limdi, N. A.
    Page, D.
    Roden, D. M.
    Wagner, M. J.
    Caldwell, M. D.
    Johnson, J. A.
    Estimation of the warfarin dose with clinical and pharmacogenetic data2009Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 360, nr 8, s. 753-764Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base.

    METHODS: Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators.

    RESULTS: In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring < or = 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring > or = 49 mg per week).

    CONCLUSIONS: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.

  • 62.
    Korsgren, Olle
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Skog, Oskar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Ludvigsson, Johnny
    Linköping University, Linköping, Sweden.
    Teplizumab in Relatives at Risk for Type 1 Diabetes2019Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, nr 19, s. 1879-1880Artikel i tidskrift (Övrigt vetenskapligt)
  • 63.
    Lagerqvist, Bo
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Frobert, Ole
    Olivecrona, Goran K.
    Gudnason, Thorarinn
    Maeng, Michael
    Alstrom, Patrik
    Andersson, Jonas
    Calais, Fredrik
    Carlsson, Jorg
    Collste, Olov
    Gotberg, Matthias
    Hardhammar, Peter
    Ioanes, Dan
    Kallryd, Anders
    Linder, Rickard
    Lundin, Anders
    Odenstedt, Jacob
    Omerovic, Elmir
    Puskar, Verner
    Todt, Tim
    Zelleroth, Eva
    Östlund, Ollie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    James, Stefan K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    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.

  • 64.
    Lagerqvist, Bo
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniskt forskningscentrum (UCR).
    James, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniskt forskningscentrum (UCR).
    Stenestrand, Ulf
    Lindbäck, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniskt forskningscentrum (UCR).
    Nilsson, Tage
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniskt forskningscentrum (UCR).
    Wallentin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniskt forskningscentrum (UCR).
    Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden2007Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 356, nr 10, s. 1009-1019Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Recent reports have indicated that there may be an increased risk of late stent thrombosis with the use of drug-eluting stents, as compared with bare-metal stents. METHODS: We evaluated 6033 patients treated with drug-eluting stents and 13,738 patients treated with bare-metal stents in 2003 and 2004, using data from the Swedish Coronary Angiography and Angioplasty Registry. The outcome analysis covering a period of up to 3 years was based on 1424 deaths and 2463 myocardial infarctions and was adjusted for differences in baseline characteristics. RESULTS: The two study groups did not differ significantly in the composite of death and myocardial infarction during 3 years of follow-up. At 6 months, there was a trend toward a lower unadjusted event rate in patients with drug-eluting stents than in those with bare-metal stents, with 13.4 fewer such events per 1000 patients. However, after 6 months, patients with drug-eluting stents had a significantly higher event rate, with 12.7 more events per 1000 patients per year (adjusted relative risk, 1.20; 95% confidence interval [CI], 1.05 to 1.37). At 3 years, mortality was significantly higher in patients with drug-eluting stents (adjusted relative risk, 1.18; 95% CI, 1.04 to 1.35), and from 6 months to 3 years, the adjusted relative risk for death in this group was 1.32 (95% CI, 1.11 to 1.57). CONCLUSIONS: Drug-eluting stents were associated with an increased rate of death, as compared with bare-metal stents. This trend appeared after 6 months, when the risk of death was 0.5 percentage point higher and a composite of death or myocardial infarction was 0.5 to 1.0 percentage point higher per year. The long-term safety of drug-eluting stents needs to be ascertained in large, randomized trials.

  • 65.
    Lonn, Eva M.
    et al.
    McMaster Univ, Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Dept Med, Hamilton, ON, Canada..
    Bosch, Jackie
    McMaster Univ, Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Sch Rehabil Sci, Hamilton, ON, Canada..
    Lopez-Jaramillo, Patricio
    Univ Santander, Fdn Oftalmol Santander, Bucaramanga, Colombia.;Univ Santander, Sch Med, Inst Masira, Bucaramanga, Colombia..
    Zhu, Jun
    Chinese Acad Med Sci, Fu Wai Hosp, Beijing 100730, Peoples R China.;Peking Union Med Coll, Beijing 100021, Peoples R China..
    Liu, Lisheng
    Chinese Acad Med Sci, Fu Wai Hosp, Beijing 100730, Peoples R China.;Peking Union Med Coll, Beijing 100021, Peoples R China..
    Pais, Prem
    St Johns Res Inst, Bangalore, Karnataka, India..
    Diaz, Rafael
    Inst Cardiovasc Rosario, Rosario, Santa Fe, Argentina..
    Xavier, Denis
    St Johns Res Inst, Bangalore, Karnataka, India.;St Johns Med Coll, Bangalore, Karnataka, India..
    Sliwa, Karen
    Univ Cape Town, Soweto Cardiovasc Res Grp, Dept Med, Hatter Inst Cardiovasc Res Africa, ZA-7925 Cape Town, South Africa..
    Dans, Antonio
    Univ Philippines, Coll Med, Manila, Philippines..
    Avezum, Alvaro
    Dante Pazzanese Inst Cardiol, Sao Paulo, Brazil..
    Piegas, Leopoldo S.
    HCor Heart Hosp, Sao Paulo, Brazil..
    Keltai, Katalin
    Semmelweis Univ, Hungarian Inst Cardiol, H-1085 Budapest, Hungary..
    Keltai, Matyas
    Semmelweis Univ, Hungarian Inst Cardiol, H-1085 Budapest, Hungary..
    Chazova, Irina
    Inst Clin Cardiol, Russian Cardiol Res Complex, Moscow, Russia..
    Peters, Ron J. G.
    Univ Amsterdam, Acad Med Ctr, Dept Cardiol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands..
    Held, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Yusoff, Khalid
    Univ Teknol Majlis Amansh Rakyat, Selayang, Malaysia.;Univ Coll Sedaya Int Univ, Kuala Lumpur, Malaysia..
    Lewis, Basil S.
    Technion Israel Inst Technol, Lady Davis Carmel Med Ctr, Ruth & Bruce Rappaport Sch Med, Haifa, Israel..
    Jansky, Petr
    Univ Hosp Motol, Prague, Czech Republic..
    Parkhomenko, Alexander
    Inst Cardiol, Kiev, Ukraine..
    Khunti, Kamlesh
    Univ Leicester, Diabet Res Ctr, Leicester, Leics, England..
    Toff, William D.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, Leicester Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Leicester, Leics, England..
    Reid, Christopher M.
    Monash Univ, Monash Ctr Cardiovasc Res & Educ Therapeut, Primary Care Diabet & Vasc Med, Melbourne, Vic 3004, Australia.;Curtin Univ, Sch Publ Hlth, Perth, WA 6845, Australia..
    Varigos, John
    Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia..
    Leiter, Lawrence A.
    Univ Toronto, St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON, Canada.;Univ Toronto, St Michaels Hosp, Keenan Res Ctr Biomed Sci, Toronto, ON, Canada..
    Molina, Dora I.
    Univ Caldas, Manizales, Colombia.;Inst Prestadora Salud Internistas Caldas, Manizales, Colombia..
    McKelvie, Robert
    McMaster Univ, Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Dept Med, Hamilton, ON, Canada..
    Pogue, Janice
    McMaster Univ, Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada..
    Wilkinson, Joanne
    McMaster Univ, Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada..
    Jung, Hyejung
    McMaster Univ, Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada..
    Dagenais, Gilles
    Univ Laval, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada..
    Yusuf, Salim
    McMaster Univ, Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Dept Med, Hamilton, ON, Canada..
    Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease2016Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 374, nr 21, s. 2009-2020Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND Antihypertensive therapy reduces the risk of cardiovascular events among high-risk persons and among those with a systolic blood pressure of 160 mm Hg or higher, but its role in persons at intermediate risk and with lower blood pressure is unclear.

    METHODS In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to receive either candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; the second coprimary outcome additionally included resuscitated cardiac arrest, heart failure, and revascularization. The median follow-up was 5.6 years.

    RESULTS The mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo group. The first coprimary outcome occurred in 260 participants (4.1%) in the active-treatment group and in 279 (4.4%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40); the second coprimary outcome occurred in 312 participants (4.9%) and 328 participants (5.2%), respectively (hazard ratio, 0.95; 95% CI, 0.81 to 1.11; P = 0.51). In one of the three prespecified hypothesis-based subgroups, participants in the subgroup for the upper third of systolic blood pressure (>143.5 mm Hg) who were in the active-treatment group had significantly lower rates of the first and second coprimary outcomes than those in the placebo group; effects were neutral in the middle and lower thirds (P = 0.02 and P = 0.009, respectively, for trend in the two outcomes).

    CONCLUSIONS Therapy with candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who did not have cardiovascular disease. ( ClinicalTrials. gov number, NCT00468923.)

  • 66.
    Lopes, Renato D.
    et al.
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Heizer, Gretchen
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Aronson, Ronald
    Bristol Myers Squibb, Princeton, NJ USA.
    Vora, Amit N.
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Massaro, Tyler
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Mehran, Roxana
    Icahn Sch Med Mt Sinai, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA;Cardiovasc Res Fdn, New York, NY USA.
    Goodman, Shaun G.
    Univ Alberta, Canadian VIGOUR Ctr, Edmonton, AB, Canada;Univ Toronto, St Michaels Hosp, Terrence Donnelly Heart Ctr, Toronto, ON, Canada.
    Windecker, Stephan
    Swiss Cardiovasc Ctr, Bern, Switzerland.
    Darius, Harald
    Vivantes Neukoelln Med Ctr, Berlin, Germany.
    Li, Jia
    Bristol Myers Squibb, Princeton, NJ USA.
    Averkov, Oleg
    Pirogov Russian Natl Res Med Univ, Moscow, Russia.
    Bahit, M. Cecilia
    Fdn INECO, Inst Neurol Cognit INECO Neurociencias Orono, Rosario, Santa Fe, Argentina.
    Berwanger, Otavio
    Hosp Israelita Albert Einstein, Sao Paulo, Brazil.
    Budaj, Andrzej
    Grochowski Hosp, Postgrad Med Sch, Warsaw, Poland.
    Hijazi, Ziad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Parkhomenko, Alexander
    Strazhesko Inst Cardiol, Natl Sci Ctr, Kiev, Ukraine.
    Sinnaeve, Peter
    Univ Leuven, Univ Hosp Leuven, Leuven, Belgium.
    Storey, Robert F.
    Univ Sheffield, Dept Infect Immun & Cardiovasc Dis, Sheffield, S Yorkshire, England.
    Thiele, Holger
    Univ Leipzig, Dept Internal Med Cardiol, Heart Ctr Leipzig, Leipzig, Germany.
    Vinereanu, Dragos
    Univ Med & Pharm Carol Davila, Univ & Emergency Hosp, Bucharest, Romania.
    Granger, Christopher B.
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Alexander, John H.
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation2019Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 380, nr 16, s. 1509-1524Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear. Methods In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y(12) inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events. Results Enrollment included 4614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P=0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group. Conclusions In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y(12) inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both.

  • 67.
    McMurray, J. J. V.
    et al.
    Univ Glasgow, BHF Cardiovasc Res Ctr, Glasgow, Lanark, Scotland.
    Solomon, S. D.
    Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA.
    Inzucchi, S. E.
    Yale Univ, Sch Med, Sect Endocrinol, New Haven, CT USA.
    Kober, L.
    Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark.
    Kosiborod, M. N.
    Univ Missouri, St Lukes Mid Amer Heart Inst, Kansas City, MO 64110 USA.
    Martinez, F. A.
    Natl Univ Cordoba, Cordoba, Argentina.
    Ponikowski, P.
    Wroclaw Med Univ, Wroclaw, Poland.
    Sabatine, M. S.
    Brigham & Womens Hosp, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Anand, I. S.
    Univ Minnesota, Dept Cardiol, Minneapolis, MN USA.
    Belohlavek, J.
    Bohm, M.
    Saarland Univ Hosp, Dept Med, Homburg, Germany.
    Chiang, C. -E
    Chopra, V. K.
    Medanta, Dept Cardiol, Gurgaon, India.
    de Boer, R. A.
    Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands;Univ Groningen, Groningen, Netherlands.
    Desai, A. S.
    Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA.
    Diez, M.
    Inst Cardiovasc Buenos Aires, Div Cardiol, Buenos Aires, DF, Argentina.
    Drozdz, J.
    Med Univ Lodz, Dept Cardiol, Lodz, Poland.
    Dukat, A.
    Comenius Univ, Dept Internal Med 5, Bratislava, Slovakia.
    Ge, J.
    Shanghai Inst Cardiovasc Dis, Dept Cardiol, Shanghai, Peoples R China;Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China.
    Howlett, J. G.
    Univ Calgary, Cumming Sch Med, Calgary, AB, Canada;Univ Calgary, Libin Cardiovasc Inst, Calgary, AB, Canada.
    Katova, T.
    Natl Cardiol Hosp, Clin Cardiol, Sofia, Bulgaria.
    Kitakaze, M.
    Natl Cerebral & Cardiovasc Ctr, Cardiovasc Div Med, Osaka, Japan.
    Ljungman, C. E. A.
    Sahlgrens Acad, Dept Mol & Clin Med & Cardiol, Gothenburg, Sweden.
    Merkely, B.
    Semmelweis Univ, Heart & Vasc Ctr, Budapest, Hungary.
    Nicolau, J. C.
    Univ Sao Paolo, Fac Med, Hosp Clin, Sao Paulo, Brazil.
    O'Meara, E.
    Montreal Heart Inst, Dept Cardiol, Montreal, PQ, Canada.
    Petrie, M. C.
    Univ Glasgow, BHF Cardiovasc Res Ctr, Glasgow, Lanark, Scotland.
    Vinh, P. N.
    Tan Tao Univ, Dept Internal Med, Tan Duc, Vietnam.
    Schou, M.
    Gentofte Univ Hosp, Dept Cardiol, Copenhagen, Denmark.
    Tereshchenko, S.
    Natl Med Res Ctr Cardiol, Dept Myocardial Dis & Heart Failure, Moscow, Russia.
    Verma, S.
    Univ Toronto, St Michaels Hosp, Div Cardiac Surg, Toronto, ON, Canada.
    Held, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    DeMets, D. L.
    Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53706 USA.
    Docherty, K. F.
    Univ Glasgow, BHF Cardiovasc Res Ctr, Glasgow, Lanark, Scotland.
    Jhund, P. S.
    Univ Glasgow, BHF Cardiovasc Res Ctr, Glasgow, Lanark, Scotland.
    Bengtsson, O.
    AstraZeneca, Gothenburg, Sweden.
    Sjostrand, M.
    AstraZeneca, Gothenburg, Sweden.
    Langkilde, A. -M
    Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction2019Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, nr 21, s. 1995-2008Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.

    METHODS In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.

    RESULTS Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.

    CONCLUSIONS Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.

  • 68.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Dyslexia1998Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 338, nr 25, s. 1853-Artikel i tidskrift (Refereegranskat)
  • 69.
    Melhus, Håkan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Serum retinol levels and fracture risk: Authors reply2003Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 348, nr 19, s. 1928-Artikel i tidskrift (Övrig (populärvetenskap, debatt, mm))
  • 70.
    Metra, Marco
    et al.
    Univ Brescia, Cardiol, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth, Brescia, Italy.
    Teerlink, John R.
    Univ Calif San Francisco, Sect Cardiol, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA;Univ Calif San Francisco, Sch Med, San Francisco, CA USA.
    Cotter, Gad
    Duke Univ, Sch Med, Momentum Res, Durham, NC USA.
    Davison, Beth A.
    Duke Univ, Sch Med, Momentum Res, Durham, NC USA.
    Felker, G. Michael
    Duke Univ, Sch Med, Div Cardiol, Durham, NC USA.
    Filippatos, Gerasimos
    Univ Cyprus, Sch Med, Nicosia, Cyprus;Univ Athens, Sch Med, Athens, Greece.
    Greenberg, Barry H.
    Univ Calif San Diego, Div Cardiol, La Jolla, CA 92093 USA.
    Pang, Peter S.
    Indiana Univ Sch Med, Dept Emergency Med, Indianapolis, IN 46202 USA;Regenstrief Inst Hlth Care, Indianapolis, IN 46202 USA.
    Ponikowski, Piotr
    Med Univ, Mil Hosp, Dept Heart Dis, Wroclaw, Poland.
    Voors, Adriaan A.
    Univ Groningen, Groningen, Netherlands.
    Adams, Kirkwood F.
    Univ N Carolina, Chapel Hill, NC 27515 USA.
    Anker, Stefan D.
    Charite Univ Med Berlin, Partner Site Berlin, Dept Internal Med & Cardiol, Campus Virchow Klinikum,German Ctr Cardiovasc Res, Berlin, Germany;Charite Univ Med Berlin, Berlin Inst Hlth Ctr Regenerat Therapies, Campus Virchow Klinikum, Berlin, Germany.
    Arias-Mendoza, Alexandra
    Inst Nacl Cardiol Ignacio Chavez, Coronary Care & Emergency Dept, Mexico City, DF, Mexico.
    Avendano, Patricio
    Hosp Clin Fuerza Aerea Chile, Las Condes, Chile.
    Bacal, Fernando
    Univ Sao Paulo, Heart Inst InCor, Heart Transplantat Dept, Sao Paulo, Brazil;Hosp Israelita Albert Einstein, Sao Paulo, Brazil.
    Boehm, Michael
    Saarland Univ, Univ Klinikum Saarlandes Homburg, Homburg, Germany.
    Bortman, Guillermo
    Sanat Trinidad Mitre, Buenos Aires, DF, Argentina.
    Cleland, John G. F.
    Univ Glasgow, Robertson Ctr Biostat & Clin Trials, Glasgow, Lanark, Scotland;Imperial Coll, Natl Heart & Lung Inst, London, England.
    Cohen-Solal, Alain
    Hop Lariboisiere, Cardiol Dept, Paris, France;Univ Paris, Paris, France.
    Crespo-Leiro, Maria G.
    Univ A Coruna, Complejo Hosp Univ A Coruna, Ctr Invest Biomed Red Enfermedades Cardiovasc, La Coruna, Spain.
    Dorobantu, Maria
    Carol Davila Univ Med & Pharm, Bucharest, Romania.
    Echeverria, Luis E.
    Fdn Cardiovasc Colombia, Heart Failure & Heart Transplant Clin, Floridablanca, Colombia.
    Ferrari, Roberto
    Univ Ferrara, Ctr Cardiol, Ferrara, Italy;Maria Cecilia Hosp, GVM Care & Res, Cotignola, Italy.
    Goland, Sorel
    Hebrew Univ Jerusalem, Kaplan Med Ctr, Heart Inst, Jerusalem, Israel.
    Goncalvesova, Eva
    Natl Cardiovasc Inst, Bratislava, Slovakia.
    Goudev, Assen
    Med Univ Sofia, Tzaritza Ioanna Univ Hosp, Sofia, Bulgaria.
    Kober, Lars
    Univ Copenhagen, Rigshosp, Dept Cardiol, Copenhagen, Denmark.
    Lema-Osores, Juan
    Hosp Nacl Arzobispo Loayza, Internal Med Cardiol, Internal Med Dept, Lima, Peru.
    Levy, Phillip D.
    Wayne State Univ, Sch Med, Detroit, MI USA;Cardiovasc Res Inst, Detroit, MI USA.
    McDonald, Kenneth
    Univ Coll Dublin, Sch Med & Med Sci, Dublin, Ireland;Univ Coll Dublin, St Vincents Univ Hosp, Dublin, Ireland.
    Manga, Pravin
    Univ Witwatersrand, Dept Internal Med, Johannesburg, South Africa.
    Merkely, Bela
    Semmelweis Univ, Heart & Vasc Ctr, Budapest, Hungary.
    Mueller, Christian
    Univ Basel, Univ Hosp Basel, Dept Cardiol, Basel, Switzerland;Univ Basel, Univ Hosp Basel, Cardiovasc Res Inst Basel, Basel, Switzerland.
    Pieske, Burkert
    Charite Univ Med Berlin, Partner Site Berlin, Dept Internal Med & Cardiol, Campus Virchow Klinikum,German Ctr Cardiovasc Res, Berlin, Germany.
    Silva-Cardoso, Jose
    Univ Porto, Med Sch, Sao Joao Med Ctr, CINTESIS, Porto, Portugal.
    Spinar, Jindrich
    Squire, Iain
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England;Glenfield Hosp, Biomed Res Ctr, Natl Inst Hlth Res, Leicester, Leics, England.
    Stepinska, Janina
    Van Mieghem, Walter
    Univ Hasselt, Hasselt, Belgium.
    von Lewinski, Dirk
    Med Univ Graz, Dept Internal Med, Div Cardiol, Graz, Austria.
    Wikström, Gerhard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Yilmaz, Mehmet B.
    Dokuz Eylul Univ, Dept Cardiol, Fac Med, Izmir, Turkey.
    Hagner, Nicole
    Novartis Pharmaceut, E Hanover, NJ USA.
    Holbro, Thomas
    Novartis Pharmaceut, Basel, Switzerland;Novartis Pharmaceut, E Hanover, NJ USA.
    Hua, Tsushung A.
    Novartis Pharmaceut, E Hanover, NJ USA.
    Sabarwal, Shalini V.
    Novartis Pharmaceut, E Hanover, NJ USA.
    Severin, Thomas
    Novartis Pharmaceut, Basel, Switzerland.
    Szecsody, Peter
    Novartis Pharmaceut, Basel, Switzerland.
    Gimpelewicz, Claudio
    Novartis Pharmaceut, Basel, Switzerland.
    y Effects of Serelaxin in Patients with Acute Heart Failure2019Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, nr 8, s. 716-726Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundSerelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. MethodsIn this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 mu g per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days.

    ResultsA total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P=0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P=0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups.

    ConclusionsIn this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.) In a randomized trial, 6545 patients with acute heart failure were assigned to either serelaxin or placebo in addition to standard care. There were no significant differences between the two groups in the incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days.

  • 71.
    Michaëlsson, Karl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Aspenberg, Per
    Linkoping Univ, Linkoping, Sweden..
    Postmenopausal Osteoporosis2016Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 374, nr 21, s. 2095-2095Artikel i tidskrift (Refereegranskat)
  • 72.
    Michaëlsson, Karl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Lithell, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Vessby, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Serum retinol levels and the risk of fracture2003Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 348, nr 4, s. 287-94Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Although studies in animals and epidemiologic studies have indicated that a high vitamin A intake is associated with increased bone fragility, no biologic marker of vitamin A status has thus far been used to assess the risk of fractures in humans. METHODS: We enrolled 2322 men, 49 to 51 years of age, in a population-based, longitudinal cohort study. Serum retinol and beta carotene were analyzed in samples obtained at enrollment. Fractures were documented in 266 men during 30 years of follow-up. Cox regression analysis was used to determine the risk of fracture according to the serum retinol level. RESULTS: The risk of fracture was highest among men with the highest levels of serum retinol. Multivariate analysis of the risk of fracture in the highest quintile for serum retinol (>75.62 microg per deciliter [2.64 micromol per liter]) as compared with the middle quintile (62.16 to 67.60 microg per deciliter [2.17 to 2.36 micromol per liter]) showed that the rate ratio was 1.64 (95 percent confidence interval, 1.12 to 2.41) for any fracture and 2.47 (95 percent confidence interval, 1.15 to 5.28) for hip fracture. The risk of fracture was further increased within the highest quintile for serum retinol. Men with retinol levels in the 99th percentile (>103.12 microg per deciliter [3.60 micromol per liter]) had an overall risk of fracture that exceeded the risk among men with lower levels by a factor of seven (P<0.001). The level of serum beta carotene was not associated with the risk of fracture. CONCLUSIONS: Our findings, which are consistent with the results of studies in animals, as well as in vitro and epidemiologic dietary studies, suggest that current levels of vitamin A supplementation and food fortification in many Western countries may need to be reassessed.

  • 73. Moffatt, Miriam F
    et al.
    Gut, Ivo G
    Demenais, Florence
    Strachan, David P
    Bouzigon, Emmanuelle
    Heath, Simon
    von Mutius, Erika
    Farrall, Martin
    Lathrop, Mark
    Cookson, William O C M
    A large-scale, consortium-based genomewide association study of asthma2010Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 363, nr 13, s. 1211-1221Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma.

  • 74. Mäki, Markku
    et al.
    Mustalahti, Kirsi
    Kokkonen, Jorma
    Kulmala, Petri
    Haapalahti, Mila
    Karttunen, Tuomo
    Ilonen, Jorma
    Laurila, Kaija
    Dahlbom, Ingrid
    Pharmacia Diagnostics.
    Hansson, Tony
    Pharmacia Diagnostics.
    Höpfl, Peter
    Knip, Mikael
    Prevalence of Celiac disease among children in Finland2003Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 348, nr 25, s. 2517-2524Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Wheat, rye, and barley proteins induce celiac disease, an autoimmune type of gastrointestinal disorder, in genetically susceptible persons. Because the disease may be underdiagnosed, we estimated the prevalence of the disease and tested the hypothesis that assays for serum autoantibodies can be used to detect untreated celiac disease and that positive findings correlate with specific HLA haplotypes.

    METHODS: Serum samples were collected from 3654 students (age range, 7 to 16 years) in 1994 and screened in 2001 for endomysial and tissue transglutaminase antibodies. HLA typing was also performed on stored blood samples. All antibody-positive subjects were asked to undergo small-bowel biopsy in 2001.

    RESULTS: Of the 3654 subjects, 56 (1.5 percent) had positive antibody tests, as determined in 2001. Results of the two antibody tests were highly concordant. As of 1994, none of the subjects had received a clinical diagnosis of celiac disease, but 10 who had positive tests for both antibodies in serum obtained in 1994 received the diagnosis between 1994 and 2001. Of the 36 other subjects with positive antibody assays who agreed to undergo biopsy in 2001, 27 had evidence of celiac disease on biopsy. Thus, the estimated biopsy-proved prevalence was 1 case in 99 children. All but two of the antibody-positive subjects had either the HLA-DQ2 or the HLA-DQ8 haplotype. The prevalence of the combination of antibody positivity and an HLA haplotype associated with celiac disease was 1 in 67.

    CONCLUSIONS: The presence of serum tissue transglutaminase and endomysial autoantibodies is predictive of small-bowel abnormalities indicative of celiac disease. There is a good correlation between autoantibody positivity and specific HLA haplotypes. We estimate that the prevalence of celiac disease among Finnish schoolchildren is at least 1 case in 99 children.

  • 75. Nathan, Carl
    et al.
    Cars, Otto
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Antibiotic resistance: problems, progress, and prospects2014Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, nr 19, s. 1761-1763Artikel i tidskrift (Övrigt vetenskapligt)
  • 76. Naucler, Pontus
    et al.
    Ryd, Walter
    Tornberg, Sven
    Strand, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Wadell, Goran
    Elfgren, Kristina
    Radberg, Thomas
    Strander, Bjorn
    Forslund, Ola
    Hansson, Bengt-Goran
    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.

  • 77. 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, P. W.
    Groop, L.
    Hall, A. S.
    Hamsten, A.
    Hengstenberg, C.
    Hovingh, G. Kees
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    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, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    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.
    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.

  • 78.
    Neumann, J. T.
    et al.
    Univ Heart Ctr Hamburg, Hamburg, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.
    Twerenbold, R.
    Univ Heart Ctr Hamburg, Hamburg, Germany;Univ Basel, Univ Hosp Basel, Cardiovasc Res Inst Basel, Basel, Switzerland;Univ Basel, Univ Hosp Basel, Dept Cardiol, Basel, Switzerland.
    Ojeda, F.
    Univ Heart Ctr Hamburg, Hamburg, Germany.
    Sörensen, N. A.
    Univ Heart Ctr Hamburg, Hamburg, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.
    Chapman, A. R.
    Univ Edinburgh, British Heart Fdn, Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland.
    Shah, A. S. V.
    Univ Edinburgh, British Heart Fdn, Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland;Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.
    Anand, A.
    Univ Edinburgh, British Heart Fdn, Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland.
    Boeddinghaus, J.
    Univ Basel, Univ Hosp Basel, Cardiovasc Res Inst Basel, Basel, Switzerland;Univ Basel, Univ Hosp Basel, Dept Cardiol, Basel, Switzerland.
    Nestelberger, T.
    Univ Basel, Univ Hosp Basel, Cardiovasc Res Inst Basel, Basel, Switzerland;Univ Basel, Univ Hosp Basel, Dept Cardiol, Basel, Switzerland.
    Badertscher, P.
    Univ Basel, Univ Hosp Basel, Cardiovasc Res Inst Basel, Basel, Switzerland;Univ Basel, Univ Hosp Basel, Dept Cardiol, Basel, Switzerland.
    Mokhtari, A.
    Lund Univ, Skane Univ Hosp, Dept Internal & Emergency Med, Lund, Sweden.
    Pickering, J. W.
    Univ Otago Christchurch, Dept Med, Christchurch, New Zealand;Christchurch Hosp, Emergency Dept, Christchurch, New Zealand.
    Troughton, R. W.
    Univ Otago Christchurch, Dept Med, Christchurch, New Zealand;Christchurch Hosp, Emergency Dept, Christchurch, New Zealand.
    Greenslade, J.
    Royal Brisbane & Womens Hosp, Dept Emergency Med, Herston, Qld, Australia;Queensland Univ Technol, Inst Hlth & Biomed Innovat, Kelvin Grove, Australia.
    Parsonage, W.
    Royal Brisbane & Womens Hosp, Cardiol, Herston, Qld, Australia;Queensland Univ Technol, Inst Hlth & Biomed Innovat, Kelvin Grove, Australia.
    Mueller-Hennessen, M.
    Heidelberg Univ Hosp, Dept Cardiol, Heidelberg, Germany;DZHK Partner Site Heidelberg Mannheim, Heidelberg, Germany.
    Gori, T.
    Johannes Gutenberg Univ Mainz, Cardiol 1, Univ Med Ctr, Mainz, Germany.
    Jernberg, T.
    Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Stockholm, Sweden.
    Morris, N.
    Univ Manchester, Manchester, Lancs, England;Manchester Univ Fdn Trust, Manchester, Lancs, England.
    Liebetrau, C.
    Kerckhoff Heart & Thorax Ctr, DZHK Partner Site Rhine Main, Bad Nauheim, Germany;Kerckhoff Heart & Thorax Ctr, Dept Cardiol, Bad Nauheim, Germany;Justus Liebig Univ Giessen & Marburg, Dept Cardiol, Giessen, Germany.
    Hamm, C.
    Kerckhoff Heart & Thorax Ctr, DZHK Partner Site Rhine Main, Bad Nauheim, Germany;Kerckhoff Heart & Thorax Ctr, Dept Cardiol, Bad Nauheim, Germany;Justus Liebig Univ Giessen & Marburg, Dept Cardiol, Giessen, Germany.
    Katus, H. A.
    Heidelberg Univ Hosp, Dept Cardiol, Heidelberg, Germany;DZHK Partner Site Heidelberg Mannheim, Heidelberg, Germany.
    Münzel, T.
    Johannes Gutenberg Univ Mainz, Cardiol 1, Univ Med Ctr, Mainz, Germany.
    Landmesser, U.
    Charite Univ Med Berlin, Campus Benjamin Franklin, Berlin Inst Hlth, Dept Cardiol, Berlin, Germany;DZHK Partner Site Berlin, Berlin, Germany.
    Salomaa, V.
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Iacoviello, L.
    Ist Ricovero & Cura Carattere Sci Neuromed, Dept Epidemiol & Prevent, Pozzilli, Italy;Univ Insubria, Res Ctr Epidemiol & Prevent Med, Dept Med & Surg, Varese, Italy.
    Ferrario, M. M.
    Univ Insubria, Res Ctr Epidemiol & Prevent Med, Dept Med & Surg, Varese, Italy.
    Giampaoli, S.
    Natl Inst Hlth, Dept Cardiovasc Dysmetabol & Aging Associated Dis, Rome, Italy.
    Kee, F.
    Queens Univ Belfast, Clin Res Collaborat Publ Hlth, Belfast, Antrim, North Ireland.
    Thorand, B.
    German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum, Munich, Germany.
    Peters, A.
    German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum, Munich, Germany;DZHK Partner Site Munich Heart Alliance, Munich, Germany.
    Borchini, R.
    Univ Insubria, Res Ctr Epidemiol & Prevent Med, Dept Med & Surg, Varese, Italy.
    Jorgensen, T.
    Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark;Res Ctr Prevent & Hlth, Glostrup, Denmark;Aalborg Univ, Med Fac, Aalborg, Denmark.
    Söderberg, S.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden;Umea Univ, Heart Ctr, Cardiol, Umea, Sweden.
    Sans, S.
    Catalan Dept Hlth, Barcelona, Spain.
    Tunstall-Pedoe, H.
    Univ Dundee, Inst Cardiovasc Res, Cardiovasc Epidemiol Unit, Dundee, Scotland.
    Kuulasmaa, K.
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Renne, T.
    Univ Med Ctr Hamburg Eppendorf, Inst Clin Chem & Lab Med, Hamburg, Germany.
    Lackner, K. J.
    Univ Med Ctr Mainz, Inst Clin Chem & Lab Med, Mainz, Germany.
    Worster, A.
    McMaster Univ, Div Emergency Med, Hamilton, ON, Canada.
    Body, R.
    Univ Manchester, Manchester, Lancs, England;Manchester Univ Fdn Trust, Manchester, Lancs, England.
    Ekelund, U.
    Lund Univ, Skane Univ Hosp, Dept Internal & Emergency Med, Lund, Sweden.
    Kavsak, P. A.
    McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada.
    Keller, T.
    Kerckhoff Heart & Thorax Ctr, DZHK Partner Site Rhine Main, Bad Nauheim, Germany;Kerckhoff Heart & Thorax Ctr, Dept Cardiol, Bad Nauheim, Germany.
    Lindahl, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Wild, P.
    Johannes Gutenberg Univ Mainz, Ctr Cardiol, Prevent Cardiol & Prevent Med, Univ Med Ctr, Mainz, Germany;Johannes Gutenberg Univ Mainz, Univ Med Ctr, Ctr Thrombosis & Hemostasis, Mainz, Germany.
    Giannitsis, E.
    Heidelberg Univ Hosp, Dept Cardiol, Heidelberg, Germany;DZHK Partner Site Heidelberg Mannheim, Heidelberg, Germany.
    Than, M.
    Univ Otago Christchurch, Dept Med, Christchurch, New Zealand;Christchurch Hosp, Emergency Dept, Christchurch, New Zealand.
    Cullen, L. A.
    Royal Brisbane & Womens Hosp, Dept Emergency Med, Herston, Qld, Australia;Queensland Univ Technol, Inst Hlth & Biomed Innovat, Kelvin Grove, Australia.
    Mills, N. L.
    Univ Edinburgh, British Heart Fdn, Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland;Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.
    Mueller, C.
    Univ Basel, Univ Hosp Basel, Cardiovasc Res Inst Basel, Basel, Switzerland;Univ Basel, Univ Hosp Basel, Dept Cardiol, Basel, Switzerland.
    Zeller, T.
    Univ Heart Ctr Hamburg, Hamburg, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.
    Westermann, D.
    Univ Heart Ctr Hamburg, Hamburg, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.
    Blankenberg, S.
    Univ Heart Ctr Hamburg, Hamburg, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.
    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]

    Background: Data 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.

    Methods: In 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.

    Results: Among 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.

    Conclusions: A 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.

  • 79.
    Papadopoulos, Fotios C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Suicide and Cardiovascular Death after a Cancer Diagnosis2012Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, nr 3, s. 276-277Artikel i tidskrift (Refereegranskat)
  • 80. Perner, Anders
    et al.
    Haase, Nicolai
    Guttormsen, Anne B.
    Tenhunen, Jyrki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Klemenzson, Gudmundur
    Åneman, Anders
    Madsen, Kristian R.
    Moller, Morten H.
    Elkjaer, Jeanie M.
    Poulsen, Lone M.
    Bendtsen, Asger
    Winding, Robert
    Steensen, Morten
    Berezowicz, Pawel
    Søe-Jensen, Peter
    Bestle, Morten
    Strand, Kristian
    Wiis, Jørgen
    White, Jonathan O.
    Thornberg, Klaus J.
    Quist, Lars
    Nielsen, Jonas
    Andersen, Lasse H.
    Holst, Lars B.
    Thormar, Katrin
    Kjaeldgaard, Anne-Lene
    Fabritius, Maria L.
    Mondrup, Frederik
    Pott, Frank C.
    Møller, Thea P.
    Winkel, Per
    Wetterslev, Jørn
    Hydroxyethyl Starch 130/0.4 versus Ringer's Acetate in Severe Sepsis2012Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, nr 2, s. 124-134Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND Hydroxyethyl starch (HES) 130/0.4 is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis. METHODS In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.4 or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization. RESULTS Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.4 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.4 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline. CONCLUSIONS Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.4 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer's acetate. 

  • 81. Pirmohamed, Munir
    et al.
    Burnside, Girvan
    Eriksson, Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Jorgensen, Andrea L.
    Toh, Cheng Hock
    Nicholson, Toby
    Kesteven, Patrick
    Christersson, Christina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Wahlström, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Stafberg, Christina
    Zhang, J. Eunice
    Leathart, Julian B.
    Kohnke, Hugo
    Maitland-van der Zee, Anke H.
    Williamson, Paula R.
    Daly, Ann K.
    Avery, Peter
    Kamali, Farhad
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    A Randomized Trial of Genotype-Guided Dosing of Warfarin2013Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 369, nr 24, s. 2294-2303Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy.

    Methods: We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639GA) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.

    Results: A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR 4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).

    Conclusions: Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. 

  • 82. Pirmohamed, Munir
    et al.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Kamali, Farhad
    Genotype-Guided Dosing of Vitamin K Antagonists REPLY2014Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, nr 18, s. 1764-1765Artikel i tidskrift (Refereegranskat)
  • 83. Ranieri, V. Marco
    et al.
    Thompson, B. Taylor
    Barie, Philip S.
    Dhainaut, Jean-Francois
    Douglas, Ivor S.
    Finfer, Simon
    Gardlund, Bengt
    Marshall, John C.
    Rhodes, Andrew
    Artigas, Antonio
    Payen, Didier
    Tenhunen, Jyrki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Al-Khalidi, Hussein R.
    Thompson, Vivian
    Janes, Jonathan
    Macias, William L.
    Vangerow, Burkhard
    Williams, Mark D.
    Drotrecogin Alfa (Activated) in Adults with Septic Shock2012Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 366, nr 22, s. 2055-2064Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock.

    METHODS In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 mu g per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization.

    RESULTS At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P = 0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P = 0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P = 0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P = 0.81).

    CONCLUSIONS DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.

  • 84.
    Rawshani, Aidin
    et al.
    Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden;Swedish Natl Diabet Register, Ctr Registers Reg, Gothenburg, Sweden.
    Rawshani, Araz
    Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden;Swedish Natl Diabet Register, Ctr Registers Reg, Gothenburg, Sweden.
    Franzen, Stefan
    Univ Gothenburg, Sahlgrenska Acad, Hlth Metr Unit, Gothenburg, Sweden;Swedish Natl Diabet Register, Ctr Registers Reg, Gothenburg, Sweden.
    Sattar, Naveed
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Eliasson, Bjorn
    Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden;Swedish Natl Diabet Register, Ctr Registers Reg, Gothenburg, Sweden.
    Svensson, Ann-Marie
    Swedish Natl Diabet Register, Ctr Registers Reg, Gothenburg, Sweden.
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Swedish Med Prod Agcy, Uppsala, Sweden.
    Miftaraj, Mervete
    Swedish Natl Diabet Register, Ctr Registers Reg, Gothenburg, Sweden.
    McGuire, Darren K.
    Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Div Cardiol, Dallas, TX USA.
    Rosengren, Annika
    Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden.
    Gudbjornsdottir, Soffia
    Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden;Swedish Natl Diabet Register, Ctr Registers Reg, Gothenburg, Sweden.
    Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes2018Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, nr 7, s. 633-644Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND Patients with diabetes are at higher risk for death and cardiovascular outcomes than the general population. We investigated whether the excess risk of death and cardiovascular events among patients with type 2 diabetes could be reduced or eliminated. METHODS In a cohort study, we included 271,174 patients with type 2 diabetes who were registered in the Swedish National Diabetes Register and matched them with 1,355,870 controls on the basis of age, sex, and county. We assessed patients with diabetes according to age categories and according to the presence of five risk factors (elevated glycated hemoglobin level, elevated low-density lipoprotein cholesterol level, albuminuria, smoking, and elevated blood pressure). Cox regression was used to study the excess risk of outcomes (death, acute myocardial infarction, stroke, and hospitalization for heart failure) associated with smoking and the number of variables outside target ranges. We also examined the relationship between various risk factors and cardiovascular outcomes. RESULTS The median follow-up among all the study participants was 5.7 years, during which 175,345 deaths occurred. Among patients with type 2 diabetes, the excess risk of outcomes decreased stepwise for each risk-factor variable within the target range. Among patients with diabetes who had all five variables within target ranges, the hazard ratio for death from any cause, as compared with controls, was 1.06 (95% confidence interval [CI], 1.00 to 1.12), the hazard ratio for acute myocardial infarction was 0.84 (95% CI, 0.75 to 0.93), and the hazard ratio for stroke was 0.95 (95% CI, 0.84 to 1.07). The risk of hospitalization for heart failure was consistently higher among patients with diabetes than among controls (hazard ratio, 1.45; 95% CI, 1.34 to 1.57). In patients with type 2 diabetes, a glycated hemoglobin level outside the target range was the strongest predictor of stroke and acute myocardial infarction; smoking was the strongest predictor of death. CONCLUSIONS Patients with type 2 diabetes who had five risk- factor variables within the target ranges appeared to have little or no excess risk of death, myocardial infarction, or stroke, as compared with the general population. (Funded by the Swedish Association of Local Authorities and Regions and others.)

  • 85. Schilcher, Jorg
    et al.
    Koeppen, Veronika
    Aspenberg, Per
    Michaelsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Risk of Atypical Femoral Fracture during and after Bisphosphonate Use2014Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, nr 10, s. 974-976Artikel i tidskrift (Refereegranskat)
  • 86. Schilcher, Jorg
    et al.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Aspenberg, Per
    Bisphosphonates and Atypical Femoral Shaft Fractures REPLY2011Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 365, nr 4, s. 377-377Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Any judgment about the magnitude of a risk must be seen in relation to other risks and benefits. Women with osteoporosis run a high risk of fracture, which is substantially reduced by bisphosphonate therapy.1 The numbers needed to treat with bisphosphonates for 3 years are 91 for hip fractures and 14 for radiologic vertebral fractures.1 Without consideration of duration of use, we found that the number needed to harm given 3 years of treatment was 667 — that is, the benefits with the therapy outweigh the risks. The absolute risk of stress (atypical) fracture in our study tended to be higher with a longer duration of bisphosphonate use. With more than 2 years of treatment, the difference in absolute risk as compared with no treatment was 8 per 10,000 women per year of treatment. This estimate corresponds to a number needed to harm of 417 for a 3-year treatment period. Thus, theoretically, for each stress fracture caused, at least 30 vertebral and about 5 hip fractures will be prevented. This is reassuring. However, without a proper indication, the benefit–risk ratio with bisphosphonate use may not be advantageous.

  • 87. Schilcher, Jörg
    et al.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Aspenberg, Per
    Bisphosphonate Use and Atypical Fractures of the Femoral Shaft2011Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 364, nr 18, s. 1728-1737Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND Studies show conflicting results regarding the possible excess risk of atypical fractures of the femoral shaft associated with bisphosphonate use. METHODS In Sweden, 12,777 women 55 years of age or older sustained a fracture of the femur in 2008. We reviewed radiographs of 1234 of the 1271 women who had a subtrochanteric or shaft fracture and identified 59 patients with atypical fractures. Data on medications and coexisting conditions were obtained from national registries. The relative and absolute risk of atypical fractures associated with bisphosphonate use was estimated by means of a nationwide cohort analysis. The 59 case patients were also compared with 263 control patients who had ordinary subtrochanteric or shaft fractures. RESULTS The age-adjusted relative risk of atypical fracture was 47.3 (95% confidence interval [CI], 25.6 to 87.3) in the cohort analysis. The increase in absolute risk was 5 cases per 10,000 patient-years (95% CI, 4 to 7). A total of 78% of the case patients and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33.3 (95% CI, 14.3 to 77.8). The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. The duration of use influenced the risk (odds ratio per 100 daily doses, 1.3; 95% CI, 1.1 to 1.6). After drug withdrawal, the risk diminished by 70% per year since the last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38). CONCLUSIONS These population-based nationwide analyses may be reassuring for patients who receive bisphosphonates. Although there was a high prevalence of current bisphosphonate use among patients with atypical fractures, the absolute risk was small.

  • 88.
    Schwartz, G. G.
    et al.
    Univ Colorado, Sch Med, Div Cardiol, Box B130, Aurora, CO 80045 USA.
    Hagström, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala Univ Hosp, Uppsala, Sweden.
    Ball, Eric
    Walla Walla Clin, Walla Walla, WA USA.
    Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome2018Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, nr 22, s. 2097-2107Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-high-density lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTS The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group). CONCLUSIONS Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo.

  • 89. Serruys, Patrick W.
    et al.
    Morice, Marie-Claude
    Kappetein, A. Pieter
    Colombo, Antonio
    Holmes, David R.
    Mack, Michael J.
    Ståhle, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi.
    Feldman, Ted E.
    van den Brand, Marcel
    Bass, Eric J.
    Van Dyck, Nic
    Leadley, Katrin
    Dawkins, Keith D.
    Mohr, Friedrich W.
    Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease2009Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 360, nr 10, s. 961-972Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Percutaneous coronary intervention (PCI) involving drug-eluting stents is increasingly used to treat complex coronary artery disease, although coronary-artery bypass grafting (CABG) has been the treatment of choice historically. Our trial compared PCI and CABG for treating patients with previously untreated three-vessel or left main coronary artery disease (or both). METHODS: We randomly assigned 1800 patients with three-vessel or left main coronary artery disease to undergo CABG or PCI (in a 1:1 ratio). For all these patients, the local cardiac surgeon and interventional cardiologist determined that equivalent anatomical revascularization could be achieved with either treatment. A noninferiority comparison of the two groups was performed for the primary end point--a major adverse cardiac or cerebrovascular event (i.e., death from any cause, stroke, myocardial infarction, or repeat revascularization) during the 12-month period after randomization. Patients for whom only one of the two treatment options would be beneficial, because of anatomical features or clinical conditions, were entered into a parallel, nested CABG or PCI registry. RESULTS: Most of the preoperative characteristics were similar in the two groups. Rates of major adverse cardiac or cerebrovascular events at 12 months were significantly higher in the PCI group (17.8%, vs. 12.4% for CABG; P=0.002), in large part because of an increased rate of repeat revascularization (13.5% vs. 5.9%, P<0.001); as a result, the criterion for noninferiority was not met. At 12 months, the rates of death and myocardial infarction were similar between the two groups; stroke was significantly more likely to occur with CABG (2.2%, vs. 0.6% with PCI; P=0.003). CONCLUSIONS: CABG remains the standard of care for patients with three-vessel or left main coronary artery disease, since the use of CABG, as compared with PCI, resulted in lower rates of the combined end point of major adverse cardiac or cerebrovascular events at 1 year. (ClinicalTrials.gov number, NCT00114972.)

  • 90. Shlipak, Michael G.
    et al.
    Matsushita, Kunihiro
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Inker, Lesley A.
    Katz, Ronit
    Polkinghorne, Kevan R.
    Rothenbacher, Dietrich
    Sarnak, Mark J.
    Astor, Brad C.
    Coresh, Josef
    Levey, Andrew S.
    Gansevoort, Ron T.
    Cystatin C versus Creatinine in Determining Risk Based on Kidney Function2013Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 369, nr 10, s. 932-943Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND Adding the measurement of cystatin C to that of serum creatinine to determine the estimated glomerular filtration rate (eGFR) improves accuracy, but the effect on detection, staging, and risk classification of chronic kidney disease across diverse populations has not been determined. METHODS We performed a meta-analysis of 11 general-population studies (with 90,750 participants) and 5 studies of cohorts with chronic kidney disease (2960 participants) for whom standardized measurements of serum creatinine and cystatin C were available. We compared the association of the eGFR, as calculated by the measurement of creatinine or cystatin C alone or in combination with creatinine, with the rates of death (13,202 deaths in 15 cohorts), death from cardiovascular causes (3471 in 12 cohorts), and end-stage renal disease (1654 cases in 7 cohorts) and assessed improvement in reclassification with the use of cystatin C. RESULTS In the general-population cohorts, the prevalence of an eGFR of less than 60 ml per minute per 1.73 m(2) of body-surface area was higher with the cystatin C-based eGFR than with the creatinine-based eGFR (13.7% vs. 9.7%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes, and reclassification to a lower eGFR was associated with an increased risk. The net reclassification improvement with the measurement of cystatin C, as compared with creatinine, was 0.23 (95% confidence interval [CI], 0.18 to 0.28) for death and 0.10 (95% CI, 0.00 to 0.21) for end-stage renal disease. Results were generally similar for the five cohorts with chronic kidney disease and when both creatinine and cystatin C were used to calculate the eGFR. CONCLUSIONS The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations.

  • 91.
    Simonsson, Bengt
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Porkka, Kimmo
    Richter, Johan
    Second-Generation BCR-ABL Kinase Inhibitors in CML2010Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 363, nr 17, s. 1673-1673Artikel i tidskrift (Refereegranskat)
  • 92.
    Steg, P. Gabriel
    et al.
    Univ Paris, French Alliance Cardiovasc Trials, Dept Hosp Univ FIRE, Hop Bichat,INSERM,U1148, Paris, France;Hop St Antoine, AP HP, Paris, France;Imperial Coll, Natl Heart & Lung Inst, London, England;Royal Brompton Hosp, London, England.
    Bhatt, Deepak L.
    Brigham & Womens Hosp, Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Simon, Tabassome
    Hop St Antoine, AP HP, Paris, France;Dept Clin Pharmacol, Unite Rech Clin, Paris, France;Sorbonne Univ, Paris, France.
    Fox, Kim
    Imperial Coll, Natl Heart & Lung Inst, London, England;Royal Brompton Hosp, London, England.
    Mehta, Shamir R.
    Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada;McMaster Univ, Hamilton, ON, Canada.
    Harrington, Robert A.
    Stanford Univ, Stanford, CA 94305 USA.
    Held, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Andersson, Marielle
    AstraZeneca BioPharmaceut Res & Dev, Molndal, Sweden.
    Himmelmann, Anders
    AstraZeneca BioPharmaceut Res & Dev, Molndal, Sweden.
    Ridderstråle, Wilhelm
    AstraZeneca BioPharmaceut Res & Dev, Molndal, Sweden.
    Leonsson-Zachrisson, Maria
    AstraZeneca BioPharmaceut Res & Dev, Molndal, Sweden.
    Liu, Yuyin
    Baim Inst Clin Res, Boston, MA USA.
    Opolski, Grzegorz
    Med Univ Warsaw, Dept Cardiol, Warsaw, Poland.
    Zateyshchikov, Dmitry
    City Clin Hosp 51, State Hlth Care Agcy, Moscow, Russia.
    Ge, Junbo
    Fudan Univ, Shanghai Inst Cardiovasc Dis, Zhongshan Hosp, Shanghai, Peoples R China.
    Nicolau, Jose C.
    Univ Sao Paulo, Fac Med, Hosp Clin, Inst Coracao, Sao Paulo, Brazil.
    Corbalan, Ramon
    Pontificia Univ Catolica Chile, Fac Med, Santiago, Chile.
    Cornel, Jan H.
    Alkmaar, Dutch Network Cardiovasc Res, Northwest Clin, Utrecht, Netherlands;Radboud Univ Nijmegen, Dept Cardiol, Med Ctr, Nijmegen, Netherlands.
    Widimsky, Petr
    Charles Univ Prague, Cardioctr, Fac Med 3, Univ Hosp Kralovske Vinohrady, Prague, Czech Republic.
    Leiter, Lawrence A.
    Univ Toronto, Li Ka Shing Knowledge Inst, St Michaels Hosp, Toronto, ON, Canada.
    Ticagrelor in Patients with Stable Coronary Disease and Diabetes2019Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, nr 14, s. 1309-1320Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patients with stable coronary artery disease and diabetes were randomly assigned to receive either ticagrelor plus aspirin or placebo plus aspirin. At 40 months, the incidence of the composite efficacy outcome of cardiovascular death, myocardial infarction, or stroke was lower with ticagrelor than with placebo; the frequency of major bleeding was higher with ticagrelor. Background Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear. Methods In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria. Results A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P=0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P=0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P=0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02). Conclusions In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.).

  • 93. Stenkvist, Björn
    et al.
    Bengtsson, Ewert
    Uppsala universitet.
    Dahlqvist, Bengt
    Uppsala universitet.
    Eklund, Gunnar
    Eriksson, Olle
    Uppsala universitet.
    Jarkrans, Torsten
    Uppsala universitet.
    Nordin, Bo
    Uppsala universitet.
    Cardiac Glycosides and Breast Cancer Revised: Letter to the Editor1982Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 306, nr 8, s. 484-Artikel i tidskrift (Övrigt vetenskapligt)
  • 94.
    Strosberg, J.
    et al.
    H Lee Moffitt Canc Ctr & Res Inst, 12902 Magnolia Dr, Tampa, FL 33612 USA..
    El-Haddad, G.
    H Lee Moffitt Canc Ctr & Res Inst, 12902 Magnolia Dr, Tampa, FL 33612 USA..
    Wolin, E.
    Univ Kentucky, Markey Canc Ctr, Lexington, KY USA..
    Hendifar, A.
    Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA..
    Yao, J.
    Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA..
    Chasen, B.
    Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA..
    Mittra, E.
    Stanford Univ, Sch Med, Stanford, CA 94305 USA..
    Kunz, P. L.
    Stanford Univ, Sch Med, Stanford, CA 94305 USA..
    Kulke, M. H.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Jacene, H.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Bushnell, D.
    Univ Iowa, Iowa City, IA USA..
    O'Dorisio, T. M.
    Univ Iowa, Iowa City, IA USA..
    Baum, R. P.
    Zentralklin, Bad Berka, Germany..
    Kulkarni, H. R.
    Zentralklin, Bad Berka, Germany..
    Caplin, M.
    Royal Free Hosp, London, England..
    Lebtahi, R.
    Hop Beaujon, Clichy, France..
    Hobday, T.
    Mayo Clin Coll Med, Rochester, MN USA..
    Delpassand, E.
    Excel Diagnost Imaging Clin, Houston, TX USA..
    Van Cutsem, E.
    Univ Hosp, Leuven, Belgium.;Katholieke Univ Leuven, Leuven, Belgium..
    Benson, A.
    Robert H Lurie Comprehens Canc Ctr, Chicago, IL USA..
    Srirajaskanthan, R.
    Kings Coll Hosp NHS FDN Trust, London, England..
    Pavel, M.
    Charite, Berlin, Germany..
    Mora, J.
    Hosp Univ Bellvitge, Barcelona, Spain..
    Berlin, J.
    Vanderbilt Univ, Med Ctr, Nashville, TN USA..
    Grande, E.
    Hosp Univ Ramon & Cajal, Madrid, Spain..
    Reed, N.
    Beatson Oncol Ctr, Glasgow, Lanark, Scotland..
    Seregni, E.
    Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Milan, Italy..
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Sierra, M. Lopera
    Adv Accelerator Applicat USA, New York, NY USA..
    Santoro, P.
    Adv Accelerator Applicat USA, New York, NY USA..
    Thevenet, T.
    Adv Accelerator Applicat, St Genis Pouilly, France..
    Erion, J. L.
    Adv Accelerator Applicat USA, New York, NY USA..
    Ruszniewski, P.
    Hop Beaujon, Clichy, France..
    Kwekkeboom, D.
    Erasmus MC, Rotterdam, Netherlands..
    Krenning, E.
    Erasmus MC, Rotterdam, Netherlands..
    Phase 3 Trial of Lu-177-Dotatate for Midgut Neuroendocrine Tumors2017Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 376, nr 2, s. 125-135Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (Lu-177)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. METHODS We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either Lu-177-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (Lu-177-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. RESULTS At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the Lu-177-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the Lu-177-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the Lu-177-Dotatate group and 26 in the control group (P = 0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the Lu-177-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. CONCLUSIONS Treatment with Lu-177-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the Lu-177-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials. gov number, NCT01578239; EudraCT number 2011-005049-11.)

  • 95. Tannock, Ian F.
    et al.
    de Wit, Ronald
    Berry, William R.
    Horti, Jozsef
    Pluzanska, Anna
    Chi, Kim N.
    Oudard, Stephane
    Théodore, Christine
    James, Nicholas D.
    Turesson, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Rosenthal, Mark A.
    Eisenberger, Mario A.
    Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer2004Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 351, nr 15, s. 1502-12Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    BACKGROUND: Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced, hormone-refractory prostate cancer, but it does not improve survival. We compared such treatment with docetaxel plus prednisone in men with this disease. METHODS: From March 2000 through June 2002, 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks, 75 mg of docetaxel per square meter every three weeks, or 30 mg of docetaxel per square meter weekly for five of every six weeks. The primary end point was overall survival. Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality of life. All statistical comparisons were against mitoxantrone. RESULTS: As compared with the men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31 percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel. CONCLUSIONS: When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plus prednisone.

  • 96. Tricoci, Pierluigi
    et al.
    Huang, Zhen
    Held, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Moliterno, David J
    Armstrong, Paul W
    van de Werf, Frans
    White, Harvey D
    Aylward, Philip E
    Wallentin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Chen, Edmond
    Lokhnygina, Yuliya
    Pei, Jinglan
    Leonardi, Sergio
    Rorick, Tyrus L
    Kilian, Ann M
    Jennings, Lisa H K
    Ambrosio, Giuseppe
    Bode, Christoph
    Cequier, Angel
    Cornel, Jan H
    Diaz, Rafael
    Erkan, Aycan
    Huber, Kurt
    Hudson, Michael P
    Jiang, Lixin
    Jukema, J Wouter
    Lewis, Basil S
    Lincoff, A Michael
    Montalescot, Gilles
    Nicolau, José Carlos
    Ogawa, Hisao
    Pfisterer, Matthias
    Prieto, Juan Carlos
    Ruzyllo, Witold
    Sinnaeve, Peter R
    Storey, Robert F
    Valgimigli, Marco
    Whellan, David J
    Widimsky, Petr
    Strony, John
    Harrington, Robert A
    Mahaffey, Kenneth W
    Thrombin-receptor antagonist vorapaxar in acute coronary syndromes2012Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 366, nr 1, s. 20-33Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:

    Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation.

    METHODS:

    In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization.

    RESULTS:

    Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups.

    CONCLUSIONS:

    In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

  • 97.
    van Kuilenburg, Andre B. P.
    et al.
    Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,United Metab Dis, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,United Metab Dis, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,United Metab Dis, Amsterdam, Netherlands.
    Tarailo-Graovac, Maja
    Univ Calgary, Cumming Sch Med, Dept Biochem & Mol Biol, Calgary, AB, Canada;Univ Calgary, Cumming Sch Med, Dept Med Genet, Calgary, AB, Canada;Univ Calgary, Alberta Childrens Hosp, Res Inst, Calgary, AB, Canada.
    Richmond, Phillip A.
    Univ British Columbia, BC Childrens Hosp, Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC, Canada.
    Drogemoller, Britt I.
    Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada.
    Pouladi, Mahmoud A.
    Natl Univ Singapore, Dept Med, Singapore, Singapore;Natl Univ Singapore, Dept Physiol, Singapore, Singapore;Agcy Sci Technol & Res, Translat Lab Genet Med, Singapore, Singapore.
    Leen, Rene
    Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands.
    Brand-Arzamendi, Koroboshka
    St Michaels Hosp, Zebrafish Ctr Adv Drug Discovery, Toronto, ON, Canada;Univ Toronto, Toronto, ON, Canada.
    Dobritzsch, Doreen
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Dolzhenko, Egor
    Illumina, San Diego, CA USA.
    Eberle, Michael A.
    Illumina, San Diego, CA USA.
    Hayward, Bruce
    NIDDK, Gene Struct & Dis Sect, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA.
    Jones, Meaghan J.
    Univ British Columbia, BC Childrens Hosp, Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC, Canada.
    Karbassi, Farhad
    St Michaels Hosp, Zebrafish Ctr Adv Drug Discovery, Toronto, ON, Canada;Univ Toronto, Toronto, ON, Canada.
    Kobor, Michael S.
    Univ British Columbia, BC Childrens Hosp, Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC, Canada.
    Koster, Janet
    Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands.
    Kumari, Daman
    NIDDK, Gene Struct & Dis Sect, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA.
    Li, Meng
    St Michaels Hosp, Zebrafish Ctr Adv Drug Discovery, Toronto, ON, Canada;Univ Toronto, Toronto, ON, Canada.
    MacIsaac, Julia
    Univ British Columbia, BC Childrens Hosp, Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC, Canada.
    McDonald, Cassandra
    Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada.
    Meijer, Judith
    Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands.
    Nguyen, Charlotte
    Univ Toronto, Hosp Sick Children, Ctr Appl Genom Genet & Genome Biol, Toronto, ON, Canada;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.
    Rajan-Babu, Indhu-Shree
    Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada.
    Scherer, Stephen W.
    Univ Toronto, Hosp Sick Children, Ctr Appl Genom Genet & Genome Biol, Toronto, ON, Canada;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada;Univ Toronto, McLaughlin Ctr, Toronto, ON, Canada.
    Sim, Bernice
    Agcy Sci Technol & Res, Translat Lab Genet Med, Singapore, Singapore.
    Trost, Brett
    Univ Toronto, Hosp Sick Children, Ctr Appl Genom Genet & Genome Biol, Toronto, ON, Canada.
    Tseng, Laura A.
    Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands.
    Turkenburg, Marjolein
    Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands.
    van Vugt, Joke J. F. A.
    Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands;Project MinE ALS Sequencing Consortium, Utrecht, Netherlands.
    Veldink, Jan H.
    Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands;Project MinE ALS Sequencing Consortium, Utrecht, Netherlands.
    Walia, Jagdeep S.
    Univ Ottawa, Childrens Hosp Eastern Ontario, Dept Pediat, Div Med Genet, Ottawa, ON, Canada.
    Wang, Youdong
    St Michaels Hosp, Zebrafish Ctr Adv Drug Discovery, Toronto, ON, Canada;Univ Toronto, Toronto, ON, Canada.
    van Weeghel, Michel
    Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands.
    Wright, Galen E. B.
    Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada.
    Xu, Xiaohong
    Agcy Sci Technol & Res, Translat Lab Genet Med, Singapore, Singapore.
    Yuen, Ryan K. C.
    Univ Toronto, Hosp Sick Children, Ctr Appl Genom Genet & Genome Biol, Toronto, ON, Canada;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.
    Zhang, Jinqiu
    Agcy Sci Technol & Res, Translat Lab Genet Med, Singapore, Singapore.
    Ross, Colin J.
    Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada.
    Wasserman, Wyeth W.
    Univ British Columbia, BC Childrens Hosp, Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC, Canada;Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada.
    Geraghty, Michael T.
    Univ Ottawa, Childrens Hosp Eastern Ontario, Dept Pediat, Div Med Genet, Ottawa, ON, Canada.
    Santra, Saikat
    Birmingham Childrens Hosp, Dept Clin Inherited Metab Disorders, Birmingham, W Midlands, England.
    Wanders, Ronald J. A.
    Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,United Metab Dis, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,United Metab Dis, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,United Metab Dis, Amsterdam, Netherlands.
    Wen, Xiao-Yan
    St Michaels Hosp, Zebrafish Ctr Adv Drug Discovery, Toronto, ON, Canada;Univ Toronto, Toronto, ON, Canada;Univ Toronto, Inst Med Sci, Dept Med, Toronto, ON, Canada;Univ Toronto, Inst Med Sci, Dept Physiol, Toronto, ON, Canada;Univ Toronto, Inst Med Sci, Dept Lab Med & Pathobiol, Toronto, ON, Canada.
    Waterham, Hans R.
    Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,United Metab Dis, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,United Metab Dis, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,United Metab Dis, Amsterdam, Netherlands.
    Usdin, Karen
    NIDDK, Gene Struct & Dis Sect, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA.
    van Karnebeek, Clara D. M.
    Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,Amsterdam Gastroenterol & Metab, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Chem,United Metab Dis, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat,United Metab Dis, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Clin Genet,United Metab Dis, Amsterdam, Netherlands;Univ British Columbia, BC Childrens Hosp, Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC, Canada;Univ British Columbia, Dept Pediat, Vancouver, BC, Canada.
    Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS2019Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 380, nr 15, s. 1433-1441Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5′ untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.

  • 98. Verhoef, Talitha I.
    et al.
    Ragia, Georgia
    de Boer, Anthonius
    Barallon, Rita
    Kolovou, Genovefa
    Kolovou, Vana
    Konstantinides, Stavros
    Le Cessie, Saskia
    Maltezos, Efstratios
    van der Meer, Felix J. M.
    Redekop, William K.
    Remkes, Mary
    Rosendaal, Frits R.
    van Schie, Rianne M. F.
    Tavridou, Anna
    Tziakas, Dimitrios
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Manolopoulos, Vangelis G.
    Maitland-van der Zee, Anke H.
    A Randomized Trial of Genotype-Guided Dosing of Acenocoumarol and Phenprocoumon2013Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 369, nr 24, s. 2304-2312Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Observational evidence suggests that the use of a genotype-guided dosing algorithm may increase the effectiveness and safety of acenocoumarol and phenprocoumon therapy.

    Methods: We conducted two single-blind, randomized trials comparing a genotype-guided dosing algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1 with a dosing algorithm that included only clinical variables, for the initiation of acenocoumarol or phenprocoumon treatment in patients with atrial fibrillation or venous thromboembolism. The primary outcome was the percentage of time in the target range for the international normalized ratio (INR; target range, 2.0 to 3.0) in the 12-week period after the initiation of therapy. Owing to low enrollment, the two trials were combined for analysis. The primary outcome was assessed in patients who remained in the trial for at least 10 weeks.

    Results: A total of 548 patients were enrolled (273 patients in the genotype-guided group and 275 in the control group). The follow-up was at least 10 weeks for 239 patients in the genotype-guided group and 245 in the control group. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). There were no significant differences between the two groups for several secondary outcomes. The percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences with respect to the incidence of bleeding or thromboembolic events.

    Conclusions: Genotype-guided dosing of acenocoumarol or phenprocoumon did not improve the percentage of time in the therapeutic INR range during the 12 weeks after the initiation of therapy. 

  • 99.
    Wallentin, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Becker, Richard C.
    Budaj, Andrzej
    Cannon, Christopher P.
    Emanuelsson, Håkan
    Held, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Horrow, Jay
    Husted, Steen
    James, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Katus, Hugo
    Mahaffey, Kenneth W.
    Scirica, Benjamin M.
    Skene, Allan
    Steg, Philippe Gabriel
    Storey, Robert F.
    Harrington, Robert A.
    Freij, Anneli
    Thorsén, Mona
    Ticagrelor versus clopidogrel in patients with acute coronary syndromes2009Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 361, nr 11, s. 1045-1057Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel. METHODS: In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. RESULTS: At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. CONCLUSIONS: In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding.

  • 100.
    Wallentin, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniskt forskningscentrum (UCR).
    Emanuelsson, Håkan
    Harrington, Robert A.
    Ticagrelor versus Clopidogrel in Acute Coronary Syndromes REPLY2009Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 361, nr 24, s. 2387-2388Artikel i tidskrift (Refereegranskat)
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