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  • 1. Adami, Hans-Olov
    et al.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Johansson, Jan-Erik
    Management of Early Prostate Cancer REPLY2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, no 22, p. 2151-2151Article in journal (Refereed)
  • 2. Ahrenstedt, O
    et al.
    Knutson, L
    Nilsson, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson-Ekdahl, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Odlind, B
    Hällgren, R
    Enhanced local production of complement components in the small intestines of patients with Crohn's disease.1990In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 322, no 19, p. 1345-1349Article in journal (Refereed)
    Abstract [en]

    There is evidence that complement components may be formed locally in inflammatory lesions containing monocytes and macrophages. To investigate the role of complement in Crohn's disease we measured jejunal-fluid concentrations of the complement components C4, C3, and factor B by perfusion of a closed segment of the jejunum in 22 patients with Crohn's disease thought to be limited to the terminal ileum. The mean (+/- SEM) jejunal-fluid C4 concentration was 2.0 +/- 0.3 mg per liter, significantly higher than the mean level in 35 healthy controls (0.7 +/- 0.1 mg per liter; P less than 0.001). The mean C3 concentration was 1.0 +/- 0.1 mg per liter in the patients and 0.7 +/- 0.1 mg per liter in the controls (P less than 0.05). The factor B levels were similar in the two groups. Calculated rates of intestinal secretion of these components showed differences of the same magnitude. Leakage of protein from plasma was not increased. The jejunal-fluid:serum ratios of these complement proteins indicated that their appearance in the lumen of the jejunum was due to at least in part to local mucosal synthesis. The increased jejunal secretion of C4, but not C3 or factor B, paralleled the clinical activity of Crohn's disease. Values were normal in first-degree relatives of the patients (n = 13), patients with celiac disease (n = 8), and patients with ulcerative colitis (n = 4). We conclude that increased secretion of complement by clinically unaffected jejunal tissue in patients with Crohn's disease reflects the systemic nature of this disorder and may be due to the stimulated synthesis of complement by activated intestinal monocytes and macrophages.

  • 3. Alexander, John H.
    et al.
    Lopes, Renato D.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Kilaru, Rakhi
    He, Yaohua
    Mohan, Puneet
    Bhatt, Deepak L.
    Goodman, Shaun
    Verheugt, Freek W.
    Flather, Marcus
    Huber, Kurt
    Liaw, Danny
    Husted, Steen E.
    Lopez-Sendon, Jose
    De Caterina, Raffaele
    Jansky, Petr
    Darius, Harald
    Vinereanu, Dragos
    Cornel, Jan H.
    Cools, Frank
    Atar, Dan
    Luis Leiva-Pons, Jose
    Keltai, Matyas
    Ogawa, Hisao
    Pais, Prem
    Parkhomenko, Alexander
    Ruzyllo, Witold
    Diaz, Rafael
    White, Harvey
    Ruda, Mikhail
    Geraldes, Margarida
    Lawrence, Jack
    Harrington, Robert A.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 365, no 8, p. 699-708Article in journal (Refereed)
    Abstract [en]

    Background: Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome.

    Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events.

    Results: The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P = 0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P = 0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo.

    Conclusions: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events.

  • 4. Alexander, John H.
    et al.
    Lopes, Renato D.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Apixaban after Acute Coronary Syndrome REPLY2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 365, no 19, p. 1844-1845Article in journal (Refereed)
  • 5.
    Alimohammadi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hallgren, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pöntynen, Nora
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Szinnai, Gabor
    Shikama, Noriko
    Keller, Marcel P
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kinkel, Sarah A
    Husebye, Eystein S
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Peltonen, Leena
    Betterle, Corrado
    Perheentupa, Jaakko
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Scott, Hamish S
    Holländer, Georg A
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen2008In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 358, no 10, p. 1018-1028Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though recent studies concerning AIRE deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients with APS-1, the autoantigen responsible for hypoparathyroidism, a hallmark of APS-1 and its most common autoimmune endocrinopathy, has not yet been identified. METHODS: We performed immunoscreening of a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism, to identify patients with reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5). Subsequently, serum samples from 87 patients with APS-1 and 293 controls, including patients with other autoimmune disorders, were used to determine the frequency and specificity of autoantibodies against NALP5. In addition, the expression of NALP5 was investigated in various tissues. RESULTS: NALP5-specific autoantibodies were detected in 49% of the patients with APS-1 and hypoparathyroidism but were absent in all patients with APS-1 but without hypoparathyroidism, in all patients with other autoimmune endocrine disorders, and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells. CONCLUSIONS: NALP5 appears to be a tissue-specific autoantigen involved in hypoparathyroidism in patients with APS-1. Autoantibodies against NALP5 appear to be highly specific and may be diagnostic for this prominent component of APS-1.

  • 6.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala Univ, Uppsala, Sweden.
    Garmo, Hans
    Reg Canc Ctr Uppsala Örebro, Uppsala, Sweden.
    Radical Surgery or Watchful Waiting in Prostate Cancer Reply2019In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 380, no 11, p. 1084-1084Article in journal (Other academic)
  • 7.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Regional Cancer Center Uppsala Örebro.
    Garmo, Hans
    Regional Cancer Center Uppsala Örebro.
    Rider, Jennifer R.
    Taari, Kimmo
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nordling, Stig
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Swen-Olof
    Spangberg, Anders
    Andren, Ove
    Palmgren, Juni
    Steineck, Gunnar
    Adami, Hans-Olov
    Johansson, Jan-Erik
    Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, no 10, p. 932-942Article in journal (Refereed)
    Abstract [en]

    BackgroundRadical prostatectomy reduces mortality among men with localized prostate cancer; however, important questions regarding long-term benefit remain. MethodsBetween 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy. ResultsDuring 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P=0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age (relative risk, 0.45) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical prostatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P=0.04). ConclusionsExtended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment. (Funded by the Swedish Cancer Society and others.) The randomized Swedish trial of prostatectomy versus watchful waiting in disease detected mainly clinically (not by PSA screening) continues to show a benefit for early prostatectomy. The number of men younger than 65 needed to treat to prevent one death is now four. The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), a randomized trial of radical prostatectomy versus watchful waiting in men with localized prostate cancer diagnosed before the era of prostate-specific antigen (PSA) testing, showed a survival benefit of radical prostatectomy as compared with observation at 15 years of follow-up.(1) By contrast, the Prostate Cancer Intervention versus Observation Trial (PIVOT), initiated in the early era of PSA testing, showed that radical prostatectomy did not significantly reduce prostate cancer-specific or overall mortality after 12 years.(2) PSA screening profoundly changes the clinical domain of study. Among other considerations, the substantial additional lead time ...

  • 8.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Sch Med, Div Canc Studies, London, England;Kings Coll London, Sch Canc & Pharmaceut Sci, London, England.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Kings Coll London, Sch Med, Div Canc Studies, London, England.
    Taari, Kimmo
    Helsinki Univ Hosp, Dept Urol, Helsinki, Finland.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Nordling, Stig
    Univ Helsinki, Dept Pathol, Helsinki, Finland.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Swen-Olof
    Orebro Univ, Sch Hlth & Med Sci, Orebro, Sweden;Orebro Univ Hosp, Dept Urol, Orebro, Sweden.
    Andren, Ove
    Orebro Univ, Sch Hlth & Med Sci, Orebro, Sweden;Orebro Univ Hosp, Dept Urol, Orebro, Sweden.
    Steineck, Gunnar
    Sahlgrens Acad, Div Clin Canc Epidemiol, Gothenburg, Sweden.
    Adami, Hans-Olov
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Harvard TC Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA;Univ Oslo, Inst Hlth & Soc, Clin Effectiveness Res Grp, Oslo, Norway.
    Johansson, Jan-Erik
    Orebro Univ, Sch Hlth & Med Sci, Orebro, Sweden;Orebro Univ Hosp, Dept Urol, Orebro, Sweden.
    Radical Prostatectomy or Watchful Waiting in Prostate Cancer: 29-Year Follow-up2018In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, no 24, p. 2319-2329Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Radical prostatectomy reduces mortality among men with clinically detected localized prostate cancer, but evidence from randomized trials with long-term followup is sparse.

    METHODS We randomly assigned 695 men with localized prostate cancer to watchful waiting or radical prostatectomy from October 1989 through February 1999 and collected follow-up data through 2017. Cumulative incidence and relative risks with 95% confidence intervals for death from any cause, death from prostate cancer, and metastasis were estimated in intention-to-treat and per-protocol analyses, and numbers of years of life gained were estimated. We evaluated the prognostic value of histopathological measures with a Cox proportional-hazards model.

    RESULTS By December 31, 2017, a total of 261 of the 347 men in the radical-prostatectomy group and 292 of the 348 men in the watchful-waiting group had died; 71 deaths in the radical-prostatectomy group and 110 in the watchful-waiting group were due to prostate cancer (relative risk, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001; absolute difference in risk, 11.7 percentage points; 95% CI, 5.2 to 18.2). The number needed to treat to avert one death from any cause was 8.4. At 23 years, a mean of 2.9 extra years of life were gained with radical prostatectomy. Among the men who underwent radical prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension, and a Gleason score higher than 7 was associated with a risk that was 10 times as high as that with a score of 6 or lower (scores range from 2 to 10, with higher scores indicating more aggressive cancer).

    CONCLUSIONS Men with clinically detected, localized prostate cancer and a long life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer.

  • 9.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ruutu, Mirja
    Garmo, Hans
    Stark, Jennifer R.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nordling, Stig
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Swen-Olof
    Bratell, Stefan
    Spångberg, Anders
    Linköpings universitet.
    Palmgren, Juni
    Karolinska Inst. Institutionen för Medicinsk Epidemiologi och Biostatistik.
    Steineck, Gunnar
    Karolinska Inst. institutionen för onkologi-patologi..
    Adami, Hans-Olov
    Harvard, Department of Epidemiology.
    Johansson, Jan-Erik
    Örebro Universitet.
    Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 364, no 18, p. 1708-1717Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    In 2008, we reported that radical prostatectomy, as compared with watchful waiting, reduces the rate of death from prostate cancer. After an additional 3 years of follow-up, we now report estimated 15-year results.

    METHODS

    From October 1989 through February 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy. Follow-up was complete through December 2009, with histopathological review of biopsy and radical-prostatectomy specimens and blinded evaluation of causes of death. Relative risks, with 95% confidence intervals, were estimated with the use of a Cox proportional-hazards model.

    RESULTS

    During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died (P=0.007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (a difference of 6.1 percentage points; 95% confidence interval [CI], 0.2 to 12.0), and a relative risk with surgery of 0.62 (95% CI, 0.44 to 0.87; P=0.01). The survival benefit was similar before and after 9 years of follow-up, was observed also among men with low-risk prostate cancer, and was confined to men younger than 65 years of age. The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI, 2.6 to 18.4).

    CONCLUSIONS

    Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer. Men with extracapsular tumor growth may benefit from adjuvant local or systemic treatment.

  • 10.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ruutu, Mirja
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Sven-Olof
    Bratell, Stefan
    Spångberg, Anders
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nordling, Stig
    Garmo, Hans
    Palmgren, J
    Adami, HO
    Norlén, Bo Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Johansson, JE
    Radical prostatectomy versus watchful waiting in early prostate cancer2005In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 352, no 19, p. 1977-1944Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    In 2002, we reported the initial results of a trial comparing radical prostatectomy with watchful waiting in the management of early prostate cancer. After three more years of follow-up, we report estimated 10-year results.

    METHODS:

    From October 1989 through February 1999, 695 men with early prostate cancer (mean age, 64.7 years) were randomly assigned to radical prostatectomy (347 men) or watchful waiting (348 men). The follow-up was complete through 2003, with blinded evaluation of the causes of death. The primary end point was death due to prostate cancer; the secondary end points were death from any cause, metastasis, and local progression.

    RESULTS:

    During a median of 8.2 years of follow-up, 83 men in the surgery group and 106 men in the watchful-waiting group died (P=0.04). In 30 of the 347 men assigned to surgery (8.6 percent) and 50 of the 348 men assigned to watchful waiting (14.4 percent), death was due to prostate cancer. The difference in the cumulative incidence of death due to prostate cancer increased from 2.0 percentage points after 5 years to 5.3 percentage points after 10 years, for a relative risk of 0.56 (95 percent confidence interval, 0.36 to 0.88; P=0.01 by Gray's test). For distant metastasis, the corresponding increase was from 1.7 to 10.2 percentage points, for a relative risk in the surgery group of 0.60 (95 percent confidence interval, 0.42 to 0.86; P=0.004 by Gray's test), and for local progression, the increase was from 19.1 to 25.1 percentage points, for a relative risk of 0.33 (95 percent confidence interval, 0.25 to 0.44; P<0.001 by Gray's test).

    CONCLUSIONS:

    Radical prostatectomy reduces disease-specific mortality, overall mortality, and the risks of metastasis and local progression. The absolute reduction in the risk of death after 10 years is small, but the reductions in the risks of metastasis and local tumor progression are substantial.

  • 11. Bosch, Jackie
    et al.
    Gerstein, Hertzel C
    Dagenais, Gilles R
    Díaz, Rafael
    Dyal, Leanne
    Jung, Hyejung
    Maggiono, Aldo P
    Probstfield, Jeffrey
    Ramachandran, Ambady
    Riddle, Matthew C
    Rydén, Lars E
    Yusuf, Salim
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Tenerz, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 4, p. 309-18Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infarction or heart failure. Their effects in patients with (or at risk for) type 2 diabetes mellitus are unknown.

    METHODS: In this double-blind study with a 2-by-2 factorial design, we randomly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes to receive a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or standard care. The primary outcome was death from cardiovascular causes. The results of the comparison between n-3 fatty acids and placebo are reported here.

    RESULTS: During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72). The use of n-3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients [16.5%] vs. 1017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P=0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P=0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P=0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n-3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups.

    CONCLUSIONS: Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).

  • 12.
    Cannon, Christopher P.
    et al.
    Baim Inst Clin Res, 930 Commonwealth Ave, Boston, MA 02215 USA.;Brigham & Womens Hosp, Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Bhatt, Deepak L.
    Brigham & Womens Hosp, Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lip, Gregory Y. H.
    Univ Birmingham, Inst Cardiovasc Sci, Birmingham, W Midlands, England..
    Ellis, Stephen G.
    Cleveland Clin, Cleveland, OH 44106 USA..
    Kimura, Takeshi
    Kyoto Univ, Dept Cardiovasc Med, Kyoto, Japan..
    Maeng, Michael
    Aarhus Univ Hosp, Skejby, Denmark..
    Merkely, Bela
    Univ Heart & Vasc Ctr, Budapest, Hungary..
    Zeymer, Uwe
    Klinikum Stadt Ludwigshafen Rhein, Med Klin B, Ludwigshafen, Germany..
    Gropper, Savion
    Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany..
    Nordaby, Matias
    Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany..
    Kleine, Eva
    Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany..
    Harper, Ruth
    Boehringer Ingelheim GmbH & Co KG, Bracknell, Berks, England..
    Manassie, Jenny
    Boehringer Ingelheim GmbH & Co KG, Bracknell, Berks, England..
    Januzzi, James L.
    Baim Inst Clin Res, 930 Commonwealth Ave, Boston, MA 02215 USA.;Harvard Med Sch, Boston, MA USA.;Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA..
    ten Berg, Jurrien M.
    St Antonius Hosp, Nieuwegein, Netherlands..
    Steg, Gabriel
    Imperial Coll, London, England.;Univ Paris Diderot, French Alliance Cardiovasc Trials, F CRIN Network, DHU FIRE,INSERM,Unite 1148, Paris, France.;Hop Bichat Assistance Publ, Paris, France..
    Hohnloser, Stefan H.
    Goethe Univ Frankfurt, Dept Med, Div Cardiol, Frankfurt, Germany..
    Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 16, p. 1513-1524Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the standard of care after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, but this therapy is associated with a high risk of bleeding.

    METHODS In this multicenter trial, we randomly assigned 2725 patients with atrial fibrillation who had undergone PCI to triple therapy with warfarin plus a P2Y(12) inhibitor (clopidogrel or ticagrelor) and aspirin (for 1 to 3 months) (triple-therapy group) or dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y(12) inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg and 150-mg dual-therapy groups). Outside the United States, elderly patients (>= 80 years of age; >= 70 years of age in Japan) were randomly assigned to the 110-mg dual-therapy group or the triple-therapy group. The primary end point was a major or clinically relevant nonmajor bleeding event during follow-up (mean follow-up, 14 months). The trial also tested for the noninferiority of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin with respect to the incidence of a composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization.

    RESULTS The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group as compared with 26.9% in the triple-therapy group (hazard ratio, 0.52; 95% confidence interval [CI], 0.42 to 0.63; P<0.001 for noninferiority; P<0.001 for superiority) and 20.2% in the 150-mg dual-therapy group as compared with 25.7% in the corresponding triple-therapy group, which did not include elderly patients outside the United States (hazard ratio, 0.72; 95% CI, 0.58 to 0.88; P<0.001 for noninferiority). The incidence of the composite efficacy end point was 13.7% in the two dual-therapy groups combined as compared with 13.4% in the triple-therapy group (hazard ratio, 1.04; 95% CI, 0.84 to 1.29; P=0.005 for noninferiority). The rate of serious adverse events did not differ significantly among the groups.

    CONCLUSIONS Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y(12) inhibitor than among those who received triple therapy with warfarin, a P2Y(12) inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events.

  • 13.
    Cannon, Christopher P.
    et al.
    Baim Inst Clin Res, Boston, MA, USA.
    Lip, Gregory Y. H.
    Univ Birmingham, Birmingham, England.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation: The authors reply2018In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 378, no 5, p. 485-486Article in journal (Other academic)
  • 14. Chahal, Harvinder S.
    et al.
    Stals, Karen
    Unterlander, Martina
    Balding, David J.
    Thomas, Mark G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Kumar, Ajith V.
    Besser, G. Michael
    Atkinson, A. Brew
    Morrison, Patrick J.
    Howlett, Trevor A.
    Levy, Miles J.
    Orme, Steve M.
    Akker, Scott A.
    Abel, Richard L.
    Grossman, Ashley B.
    Burger, Joachim
    Ellard, Sian
    Korbonits, Marta
    Brief Report: AIP Mutation in Pituitary Adenomas in the 18th Century and Today2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 364, no 1, p. 43-50Article in journal (Refereed)
    Abstract [en]

    Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783, *RF 1-3* he noted an enlarged pituitary fossa. We extracted DNA from the patient's teeth and identified a germline mutation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier.

  • 15. Connolly, Stuart J
    et al.
    Camm, A John
    Halperin, Jonathan L
    Joyner, Campbell
    Alings, Marco
    Amerena, John
    Atar, Dan
    Avezum, Alvaro
    Blomström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Borggrefe, Martin
    Budaj, Andrzej
    Chen, Shih-Ann
    Ching, Chi Keong
    Commerford, Patrick
    Dans, Antonio
    Davy, Jean-Marc
    Delacrétaz, Etienne
    Di Pasquale, Giuseppe
    Diaz, Rafael
    Dorian, Paul
    Flaker, Greg
    Golitsyn, Sergey
    Gonzalez-Hermosillo, Antonio
    Granger, Christopher B
    Heidbüchel, Hein
    Kautzner, Josef
    Kim, June Soo
    Lanas, Fernando
    Lewis, Basil S
    Merino, Jose L
    Morillo, Carlos
    Murin, Jan
    Narasimhan, Calambur
    Paolasso, Ernesto
    Parkhomenko, Alexander
    Peters, Nicholas S
    Sim, Kui-Hian
    Stiles, Martin K
    Tanomsup, Supachai
    Toivonen, Lauri
    Tomcsányi, János
    Torp-Pedersen, Christian
    Tse, Hung-Fat
    Vardas, Panos
    Vinereanu, Dragos
    Xavier, Denis
    Zhu, Jun
    Zhu, Jun-Ren
    Baret-Cormel, Lydie
    Weinling, Estelle
    Staiger, Christoph
    Yusuf, Salim
    Chrolavicius, Susan
    Afzal, Rizwan
    Hohnloser, Stefan H
    Dronedarone in High-Risk Permanent Atrial Fibrillation2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 365, no 24, p. 2268-2276Article in journal (Refereed)
    Abstract [en]

    Background

    Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular anti-arrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in high-risk permanent atrial fibrillation.

    Methods

    We assigned patients who were at least 65 years of age with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The first coprimary outcome was stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second coprimary outcome was unplanned hospitalization for a cardiovascular cause or death.

    Results

    After the enrollment of 3236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P=0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P=0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P=0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P=0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P=0.02).

    Conclusions

    Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients.

  • 16. Connolly, Stuart J.
    et al.
    Ezekowitz, Michael D.
    Yusuf, Salim
    Eikelboom, John
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Parekh, Amit
    Pogue, Janice
    Reilly, Paul A.
    Themeles, Ellison
    Varrone, Jeanne
    Wang, Susan
    Alings, Marco
    Xavier, Denis
    Zhu, Jun
    Diaz, Rafael
    Lewis, Basil S.
    Darius, Harald
    Diener, Hans-Christoph
    Joyner, Campbell D.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Dabigatran versus warfarin in patients with atrial fibrillation2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 361, no 12, p. 1139-1151Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)

  • 17. Connolly, Stuart J.
    et al.
    Ezekowitz, Michael D.
    Yusuf, Salim
    Reilly, Paul A.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Newly Identified Events in the RE-LY Trial2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 363, no 19, p. 1875-1876Article in journal (Refereed)
  • 18. Connolly, Stuart J.
    et al.
    Pogue, Janice
    Hart, Robert G.
    Hohnloser, Stefan H.
    Pfeffer, Marc
    Chrolavicius, Susan
    Yusuf, Salim
    Effect of clopidogrel added to aspirin in patients with atrial fibrillation2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 360, no 20, p. 2066-2078Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Vitamin K antagonists reduce the risk of stroke in patients with atrial fibrillation but are considered unsuitable in many patients, who usually receive aspirin instead. We investigated the hypothesis that the addition of clopidogrel to aspirin would reduce the risk of vascular events in patients with atrial fibrillation. METHODS: A total of 7554 patients with atrial fibrillation who had an increased risk of stroke and for whom vitamin K-antagonist therapy was unsuitable were randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin. The primary outcome was the composite of stroke, myocardial infarction, non-central nervous system systemic embolism, or death from vascular causes. RESULTS: At a median of 3.6 years of follow-up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8% per year) and in 924 patients receiving placebo (7.6% per year) (relative risk with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel. Stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; 95% CI, 0.62 to 0.83; P<0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7% per year) and in 115 receiving placebo (0.9% per year) (relative risk, 0.78; 95% CI, 0.59 to 1.03; P=0.08). Major bleeding occurred in 251 patients receiving clopidogrel (2.0% per year) and in 162 patients receiving placebo (1.3% per year) (relative risk, 1.57; 95% CI, 1.29 to 1.92; P<0.001). CONCLUSIONS: In patients with atrial fibrillation for whom vitamin K-antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the risk of major hemorrhage. (ClinicalTrials.gov number, NCT00249873.)

  • 19. Connolly, Stuart J.
    et al.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Yusuf, Salim
    Additional Events in the RE-LY Trial2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 15, p. 1464-1465Article in journal (Refereed)
  • 20.
    Cunningham, A. L.
    et al.
    Westmead Inst Med Res, Westmead, NSW, Australia.;Univ Sydney, Sydney, NSW, Australia..
    Lal, H.
    GSK Vaccines, King Of Prussia, PA USA..
    Kovac, M.
    GSK Vaccines, Wavre, Belgium..
    Chlibek, R.
    Univ Def, Fac Mil Hlth Sci, Hradec Kralove, Czech Republic..
    Hwang, S. -J
    Diez-Domingo, J.
    Fdn Fomento Invest Sanitaria & Biomed, Vaccine Res Unit, Valencia, Spain..
    Godeaux, O.
    GSK Vaccines, Wavre, Belgium..
    Levin, M. J.
    Univ Colorado, Dept Pediat, Anschutz Med Campus, Aurora, CO USA.;Univ Colorado, Dept Med, Anschutz Med Campus, Aurora, CO USA..
    McElhaney, J. E.
    Hlth Sci North Res Inst, Sudbury, ON, Canada..
    Puig-Barbera, J.
    Fdn Fomento Invest Sanitaria & Biomed, Vaccine Res Unit, Valencia, Spain..
    Abeele, C. Vanden
    GSK Vaccines, Wavre, Belgium..
    Vesikari, T.
    Univ Tampere, Vaccine Res Ctr, Tampere, Finland..
    Watanabe, D.
    Aichi Med Univ, Dept Dermatol, Nagakute, Aichi, Japan..
    Zahaf, T.
    GSK Vaccines, Wavre, Belgium..
    Ahonen, A.
    Univ Tampere, Vaccine Res Ctr, Tampere, Finland..
    Athan, E.
    Deakin Univ, Barwon Hlth, Dept Infect Dis, Geelong, Vic, Australia..
    Barba-Gomez, J. F.
    Inst Dermatol Jalisco Dr Jose Barba Rubio, Zapopan, Mexico..
    Campora, L.
    GSK Vaccines, Wavre, Belgium..
    de Looze, F.
    Univ Queensland, Sch Med, AusTrials, Brisbane, Qld, Australia.;Univ Queensland, Sch Med, Discipline Gen Practice, Brisbane, Qld, Australia..
    Downey, H. J.
    Jacksonville Ctr Clin Res, Jacksonville, FL USA..
    Ghesquiere, W.
    Univ British Columbia, Infect Dis Sect, Victoria, BC, Canada..
    Gorfinkel, I.
    PrimeHlth Clin Res, Toronto, ON, Canada..
    Korhonen, T.
    Univ Tampere, Vaccine Res Ctr, Tampere, Finland..
    Leung, E.
    United Christian Hosp, Dept Med & Geriatr, Div Geriatr Med, Hong Kong, Hong Kong, Peoples R China..
    McNeil, S. A.
    Dalhousie Univ, IWK Hlth Ctr, Canadian Ctr Vaccinol, Halifax, NS, Canada.;Dalhousie Univ, Nova Scotia Hlth Author, Halifax, NS, Canada..
    Oostvogels, L.
    GSK Vaccines, Wavre, Belgium..
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Sormland Cty Council, Clin Res Ctr, Eskilstuna, Sweden..
    Smetana, J.
    Univ Def, Fac Mil Hlth Sci, Hradec Kralove, Czech Republic..
    Weckx, L.
    Univ Fed Sao Paulo, Ctr Referencia Imunobiol Especiais, Sao Paulo, Brazil..
    Yeo, W.
    Univ Wollongong, Grad Sch Med, Illawarra Hlth & Med Res Inst, Wollongong, NSW, Australia..
    Heineman, T. C.
    GSK Vaccines, King Of Prussia, PA USA..
    Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older2016In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 375, no 11, p. 1019-1032Article in journal (Refereed)
    Abstract [en]

    BACKGROUND A trial involving adults 50 years of age or older (ZOE-50) showed that the herpes zoster subunit vaccine (HZ/su) containing recombinant varicella-zoster virus glycoprotein E and the AS01(B) adjuvant system was associated with a risk of herpes zoster that was 97.2% lower than that associated with placebo. A second trial was performed concurrently at the same sites and examined the safety and efficacy of HZ/su in adults 70 years of age or older (ZOE-70). METHODS This randomized, placebo-controlled, phase 3 trial was conducted in 18 countries and involved adults 70 years of age or older. Participants received two doses of HZ/su or placebo (assigned in a 1: 1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster and postherpetic neuralgia was assessed in participants from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50. RESULTS In ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either HZ/su (6950 participants) or placebo (6950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person-years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001) and was similar in participants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%). In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P<0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P<0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two study groups. CONCLUSIONS In our trial, HZ/su was found to reduce the risks of herpes zoster and postherpetic neuralgia among adults 70 years of age or older. (Funded by GlaxoSmithKline Biologicals; ZOE-50 and ZOE-70 ClinicalTrials.govnumbers, NCT01165177 and NCT01165229.)

  • 21. Demoulin, Jean-Baptiste
    et al.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Scleroderma2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 361, no 8, p. 826-827Article in journal (Refereed)
    Abstract [en]

    In their review article on scleroderma, Gabrielli et al. incorporate their earlier observations that all patients with this disease have activating antibodies to platelet-derived growth factor (PDGF) receptors (PDGFRs). These antibodies were described as being specific for scleroderma and for chronic extensive graft-versus-host disease, two conditions that share some clinical features. The review does not reflect the current debate on the existence of such antibodies. Researchers from several centers, including ours, have challenged the results of Gabrielli et al.

  • 22. Druker, Brian J.
    et al.
    Guilhot, Francois
    O'Brien, Stephen G.
    Gathmann, Insa
    Kantarjian, Hagop
    Gattermann, Norbert
    Deininger, Michael W. N.
    Silver, Richard T.
    Goldman, John M.
    Stone, Richard M.
    Cervantes, Francisco
    Hochhaus, Andreas
    Powell, Bayard L.
    Gabrilove, Janice L.
    Rousselot, Philippe
    Reiffers, Josy
    Cornelissen, Jan J.
    Hughes, Timothy
    Agis, Hermine
    Fischer, Thomas
    Verhoef, Gregor
    Shepherd, John
    Saglio, Giuseppe
    Gratwohl, Alois
    Nielsen, Johan L.
    Radich, Jerald P.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Taylor, Kerry
    Baccarani, Michele
    So, Charlene
    Letvak, Laurie
    Larson, Richard A.
    Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia2006In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 355, no 23, p. 2408-2417Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy. METHODS: We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events. RESULTS: The median follow-up was 60 months. Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P<0.001). Grade 3 or 4 adverse events diminished over time, and there was no clinically significant change in the profile of adverse events. CONCLUSIONS: After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients. (ClinicalTrials.gov number, NCT00006343 [ClinicalTrials.gov].)

  • 23.
    Eich, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lundgren, Torbjörn
    Visualization of early engraftment in clinical islet transplantation by positron-emission tomography2007In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 356, no 26, p. 2754-2755Article in journal (Refereed)
  • 24.
    Erlinge, D.
    et al.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Omerovic, E.
    Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Fröbert, O.
    Rebro Univ, Fac Hlth, Dept Cardiol, Orebro, Sweden..
    Linder, R.
    Danderyd Hosp, Dept Cardiol, Danderyd, Sweden..
    Danielewicz, M.
    Karlstad Hosp, PCI Unit, Karlstad, Sweden..
    Hamid, M.
    Malarsjukhuset, Dept Cardiol, Eskilstuna, Sweden..
    Swahn, E.
    Linkoping Univ Hosp, Dept Cardiol, Linkoping, Sweden..
    Henareh, L.
    Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Wagner, H.
    Helsingborg Lasarett, Dept Cardiol, Helsingborg, Sweden..
    Hårdhammar, P.
    Halmstad Cty Hosp, Dept Cardiol, Halmstad, Sweden..
    Sjögren, I.
    Falun Cent Hosp, Dept Cardiol, Falun, Sweden..
    Stewart, J.
    Skaraborgs Hosp, Dept Cardiol, Skovde, Sweden..
    Grimfjärd, P.
    Vastmanlands Sjukhus, Dept Internal Med, Vasteras, Sweden..
    Jensen, J.
    Karolinska Inst, Capio St Gorans Hosp, Dept Cardiol, Stockholm, Sweden..
    Aasa, M.
    Sodersjukhuset AB, Dept Cardiol, Stockholm, Sweden..
    Robertsson, L.
    Sodra Alvsborgs Sjukhus, Dept Cardiol, Boras, Sweden..
    Lindroos, P.
    Karolinska Inst, Capio St Gorans Hosp, Dept Cardiol, Stockholm, Sweden..
    Haupt, J.
    Sunderby Sjukhus, Dept Cardiol, Lulea, Sweden..
    Wikström, H.
    Kristianstad Hosp, Dept Cardiol, Kristianstad, Sweden..
    Ulvenstam, A.
    Ostersund Hosp, Dept Cardiol, Ostersund, Sweden..
    Bhiladvala, P.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Lindvall, B.
    Sundsvall Hosp, Dept Cardiol, Sundsvall, Sweden..
    Lundin, A.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Tödt, T.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Ioanes, D.
    Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Råmunddal, T.
    Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Kellerth, T.
    Rebro Univ, Fac Hlth, Dept Cardiol, Orebro, Sweden..
    Zagozdzon, L.
    Rebro Univ, Fac Hlth, Dept Cardiol, Orebro, Sweden..
    Götberg, M.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Andersson, J.
    Umea Univ, Dept Cardiol, Umea, Sweden..
    Angerås, O.
    Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Östlund, Ollie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Schersten, F.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Eriksson, P.
    Umea Univ, Dept Cardiol, Umea, Sweden..
    Koul, S.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Bivalirudin versus Heparin Monotherapy in Myocardial Infarction2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 12, p. 1132-1142Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The comparative efficacy of various anticoagulation strategies has not been clearly established in patients with acute myocardial infarction who are undergoing percutaneous coronary intervention (PCI) according to current practice, which includes the use of radial-artery access for PCI and administration of potent P2Y 12 inhibitors without the planned use of glycoprotein IIb/IIIa inhibitors. METHODS In this multicenter, randomized, registry-based, open-label clinical trial, we enrolled patients with either ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) who were undergoing PCI and receiving treatment with a potent P2Y(12) inhibitor (ticagrelor, prasugrel, or cangrelor) without the planned use of glycoprotein IIb/IIIa inhibitors. The patients were randomly assigned to receive bivalirudin or heparin during PCI, which was performed predominantly with the use of radial-artery access. The primary end point was a composite of death from any cause, myocardial infarction, or major bleeding during 180 days of follow-up. RESULTS A total of 6006 patients (3005 with STEMI and 3001 with NSTEMI) were enrolled in the trial. At 180 days, a primary end-point event had occurred in 12.3% of the patients (369 of 3004) in the bivalirudin group and in 12.8% (383 of 3002) in the heparin group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.10; P = 0.54). The results were consistent between patients with STEMI and those with NSTEMI and across other major subgroups. Myocardial infarction occurred in 2.0% of the patients in the bivalirudin group and in 2.4% in the heparin group (hazard ratio, 0.84; 95% CI, 0.60 to 1.19; P = 0.33), major bleeding in 8.6% and 8.6%, respectively (hazard ratio, 1.00; 95% CI, 0.84 to 1.19; P = 0.98), definite stent thrombosis in 0.4% and 0.7%, respectively (hazard ratio, 0.54; 95% CI, 0.27 to 1.10; P = 0.09), and death in 2.9% and 2.8%, respectively (hazard ratio, 1.05; 95% CI, 0.78 to 1.41; P = 0.76). CONCLUSIONS Among patients undergoing PCI for myocardial infarction, the rate of the composite of death from any cause, myocardial infarction, or major bleeding was not lower among those who received bivalirudin than among those who received heparin monotherapy. (Funded by the Swedish Heart-Lung Foundation and others;

  • 25.
    Erlinge, David
    et al.
    Lund Univ, Lund, Sweden.
    James, Stefan K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Correspondence: Bivalirudin versus Heparin Monotherapy in Myocardial Infarction2018In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 378, no 3, p. 300-300Article in journal (Refereed)
  • 26.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Falk Delgado, Anna
    Melanoma Sentinel-Node Metastasis.2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 9, p. 891-2Article in journal (Refereed)
  • 27.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Falk Delgado, Anna
    Karolinska Inst, Stockholm, Sweden..
    Melanoma Sentinel-Node Metastasis2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 9, p. 891-892Article in journal (Other academic)
  • 28. Fassnacht, Martin
    et al.
    Terzolo, Massimo
    Allolio, Bruno
    Baudin, Eric
    Haak, Harm
    Berruti, Alfredo
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schade-Brittinger, Carmen
    Lacroix, André
    Jarzab, Barbara
    Sorbye, Halfdan
    Torpy, David J
    Stepan, Vinzenz
    Schteingart, David E
    Arlt, Wiebke
    Kroiss, Matthias
    Leboulleux, Sophie
    Sperone, Paola
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Hermsen, Ilse
    Hahner, Stefanie
    Willenberg, Holger S
    Tabarin, Antoine
    Quinkler, Marcus
    de la Fouchardière, Christelle
    Schlumberger, Martin
    Mantero, Franco
    Weismann, Dirk
    Beuschlein, Felix
    Gelderblom, Hans
    Wilmink, Hanneke
    Sender, Monica
    Edgerly, Maureen
    Kenn, Werner
    Fojo, Tito
    Müller, Hans-Helge
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Combination chemotherapy in advanced adrenocortical carcinoma2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 366, no 23, p. 2189-2197Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment.

    METHODS:

    We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival.

    RESULTS:

    For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments.

    CONCLUSIONS:

    Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival.

  • 29.
    Fellström , Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan G.
    Scmieder, R.E.
    Holdaas, H.
    Bannister, K.
    Beutler, J.
    Chae, D.W.
    Chevalie, A.
    Cobbe, S.M.
    Grönhagen-Riska, C.
    De Lima, J.J.
    Lins, R.
    Mayer, G.
    McMahon, A.W.
    Parving, H.H.
    Remuzzi, G.
    Samuelsson, O.
    Sonkodi, S.
    Sci, D.
    Süleymanlar, G.
    Tsakiris, D.
    Tesar, V.
    Todorov, V.
    Wiecek, A.
    Wüthrich, R.P.
    Gottlow, M.
    Johnsson, E.
    Zannard, F.
    Rosuvastatin and Cardiovascuular Events in Patients Undergoing Hemodialysis2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 360, no 14, p. 1395-1407Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved. METHODS: We conducted an international, multicenter, randomized, double-blind, prospective trial involving 2776 patients, 50 to 80 years of age, who were undergoing maintenance hemodialysis. We randomly assigned patients to receive rosuvastatin, 10 mg daily, or placebo. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points included death from all causes and individual cardiac and vascular events. RESULTS: After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg per deciliter (2.6 mmol per liter). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P=0.59). Rosuvastatin had no effect on individual components of the primary end point. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.51). CONCLUSIONS: In patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

  • 30.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan
    Holdaas, Hallvard
    Rosuvastatin in Patients Undergoing Hemodialysis REPLY2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 361, no 1, p. 94-95Article in journal (Refereed)
  • 31. Frisch, Morten
    et al.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    van der Brule, Adriaan J.C.
    Wohlfahrt, Jan
    Meijer, Chris J. L. M.
    Walboomers, Jan M. M.
    Goldman, Sven
    Svensson, Christer
    Adami, Hans-Olov
    Melbye, Mads
    Sexually transmitted infection as a cause of anal cancer1997In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 337, no 19, p. 1350-1358Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The incidence of anal cancer has increased in recent decades, particularly among women. To identify underlying risk factors, we conducted a population-based case-control study in Denmark and Sweden. METHODS: We conducted telephone interviews with 324 women and 93 men in whom invasive or in situ anal cancer was diagnosed between 1991 and 1994, 534 controls with adenocarcinoma of the rectum, and 554 population controls. The interviews covered a wide spectrum of possible risk factors for anal cancer. Odds ratios were calculated by logistic regression. Specimens of anal-cancer tissue and samples of rectal adenocarcinomas were tested for human papillomavirus (HPV) DNA with the polymerase chain reaction. RESULTS: Multivariate analysis revealed consistent and statistically significant associations between measures of sexual promiscuity and the risk of anal cancer in both men and women. There was a significant trend toward an association between higher numbers of partners of the opposite sex in women (P<0.001) and men (P<0.05) and strong associations with a variety of venereal diseases. In women, receptive anal intercourse, particularly before the age of 30 years, and venereal infections in the partner were also associated with an increased risk (odds ratios, 3.4 and 2.4, respectively). Fifteen percent of the men with anal cancer reported having had homosexual contact, as compared with none of the controls (P<0.001). High-risk types of HPV, notably HPV-16, were detected in 84 percent of the anal-cancer specimens examined, whereas all rectal-adenocarcinoma specimens tested were negative for HPV. CONCLUSIONS: Our study provides strong evidence that a sexually transmitted infection causes anal cancer. The presence of high-risk types of HPV, notably HPV-16 (which is known to cause cancer of the cervix), in the majority of anal-cancer tissue specimens suggests that most anal cancers are potentially preventable.

  • 32. Frobert, Ole
    et al.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Olivecrona, Goran K.
    Omerovic, Elmir
    Gudnason, Thorarinn
    Maeng, Michael
    Aasa, Mikael
    Angeras, Oskar
    Calais, Fredrik
    Danielewicz, Mikael
    Erlinge, David
    Hellsten, Lars
    Jensen, Ulf
    Johansson, Agneta C.
    Karegren, Amra
    Nilsson, Johan
    Robertson, Lotta
    Sandhall, Lennart
    Sjogren, Iwar
    Östlund, Ollie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Harnek, Jan
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Thrombus Aspiration during ST-Segment Elevation Myocardial Infarction2013In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 369, no 17, p. 1587-1597Article in journal (Refereed)
    Abstract [en]

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

  • 33. Fröbert, Ole
    et al.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Thrombus Aspiration during Myocardial Infarction REPLY2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, no 7, p. 675-676Article in journal (Refereed)
  • 34. Försth, Peter
    Efficacy of fusion surgery for lumbar spinal stenosis- Clinical and economic results from a 2-year multicenter randomised controlled trial in sweden.2015In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406Article in journal (Other academic)
  • 35.
    Försth, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sandén, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Fusion Surgery for Lumbar Spinal Stenosis REPLY2016In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 375, no 6, p. 599-600Article in journal (Other academic)
  • 36.
    Försth, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sandén, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    More on Fusion Surgery for Lumbar Spinal Stenosis2016In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 375, no 18, p. 1806-1807Article in journal (Refereed)
  • 37.
    Försth, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Stockholm Spine Ctr, S-10401 Stockholm, Sweden..
    Olafsson, Gylfi
    Karolinska Inst, Dept Learning Informat Management & Eth, S-10401 Stockholm, Sweden.;Quantify Res, Stockholm, Sweden..
    Carlsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Frost, Anders
    Karolinska Inst, Stockholm Spine Ctr, S-10401 Stockholm, Sweden..
    Borgstrom, Fredrik
    Karolinska Inst, Dept Learning Informat Management & Eth, S-10401 Stockholm, Sweden.;Quantify Res, Stockholm, Sweden..
    Fritzell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Futurum Acad Hlth & Care, Neuroorthoped Ctr, Ryhov, Sweden..
    Öhagen, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Michaelsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Sanden, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    A Randomized, Controlled Trial of Fusion Surgery for Lumbar Spinal Stenosis2016In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 374, no 15, p. 1413-1423Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The efficacy of fusion surgery in addition to decompression surgery in patients who have lumbar spinal stenosis, with or without degenerative spondylolisthesis, has not been substantiated in controlled trials.

    METHODS We randomly assigned 247 patients between 50 and 80 years of age who had lumbar spinal stenosis at one or two adjacent vertebral levels to undergo either decompression surgery plus fusion surgery (fusion group) or decompression surgery alone (decompression-alone group). Randomization was stratified according to the presence of preoperative degenerative spondylolisthesis (in 135 patients) or its absence. Outcomes were assessed with the use of patient-reported outcome measures, a 6-minute walk test, and a health economic evaluation. The primary outcome was the score on the Oswestry Disability Index (ODI; which ranges from 0 to 100, with higher scores indicating more severe disability) 2 years after surgery. The primary analysis, which was a per-protocol analysis, did not include the 14 patients who did not receive the assigned treatment and the 5 who were lost to follow-up.

    RESULTS There was no significant difference between the groups in the mean score on the ODI at 2 years (27 in the fusion group and 24 in the decompression-alone group, P = 0.24) or in the results of the 6-minute walk test (397 m in the fusion group and 405 m in the decompression- alone group, P = 0.72). Results were similar between patients with and those without spondylolisthesis. Among the patients who had 5 years of follow-up and were eligible for inclusion in the 5-year analysis, there were no significant differences between the groups in clinical outcomes at 5 years. The mean length of hospitalization was 7.4 days in the fusion group and 4.1 days in the decompression-alone group (P< 0.001). Operating time was longer, the amount of bleeding was greater, and surgical costs were higher in the fusion group than in the decompression-alone group. During a mean follow-up of 6.5 years, additional lumbar spine surgery was performed in 22% of the patients in the fusion group and in 21% of those in the decompression-alone group.

    CONCLUSIONS Among patients with lumbar spinal stenosis, with or without degenerative spondylolisthesis, decompression surgery plus fusion surgery did not result in better clinical outcomes at 2 years and 5 years than did decompression surgery alone.

  • 38. Genovese, Giulio
    et al.
    Kaehler, Anna K.
    Handsaker, Robert E.
    Lindberg, Johan
    Rose, Samuel A.
    Bakhoum, Samuel F.
    Chambert, Kimberly
    Mick, Eran
    Neale, Benjamin M.
    Fromer, Menachem
    Purcell, Shaun M.
    Svantesson, Oscar
    Landen, Mikael
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Gabriel, Stacey B.
    Moran, Jennifer L.
    Lander, Eric S.
    Sullivan, Patrick F.
    Sklar, Pamela
    Groenberg, Henrik
    Hultman, Christina M.
    McCarroll, Steven A.
    Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 26, p. 2477-2487Article in journal (Refereed)
    Abstract [en]

    Background Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. Methods We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. Results Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow-biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. Conclusions Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers.

  • 39. Gerstein, Hertzel C
    et al.
    Bosch, Jackie
    Dagenais, Gilles R
    Díaz, Rafael
    Jung, Hyejung
    Maggioni, Aldo P
    Pogue, Janice
    Probstfield, Jeffrey
    Ramachandran, Ambady
    Riddle, Matthew C
    Rydén, Lars E
    Yusuf, Salim
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Tenerz, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Basal insulin and cardiovascular and other outcomes in dysglycemia.2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 4, p. 319-28Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events, but such a possibility has not been formally tested.

    METHODS: We randomly assigned 12,537 people (mean age, 63.5 years) with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes to receive insulin glargine (with a target fasting blood glucose level of ≤95 mg per deciliter [5.3 mmol per liter]) or standard care and to receive n-3 fatty acids or placebo with the use of a 2-by-2 factorial design. The results of the comparison between insulin glargine and standard care are reported here. The coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure. Microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers were also compared between groups.

    RESULTS: The median follow-up was 6.2 years (interquartile range, 5.8 to 6.7). Rates of incident cardiovascular outcomes were similar in the insulin-glargine and standard-care groups: 2.94 and 2.85 per 100 person-years, respectively, for the first coprimary outcome (hazard ratio, 1.02; 95% confidence interval [CI], 0.94 to 1.11; P=0.63) and 5.52 and 5.28 per 100 person-years, respectively, for the second coprimary outcome (hazard ratio, 1.04; 95% CI, 0.97 to 1.11; P=0.27). New diabetes was diagnosed approximately 3 months after therapy was stopped among 30% versus 35% of 1456 participants without baseline diabetes (odds ratio, 0.80; 95% CI, 0.64 to 1.00; P=0.05). Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years. Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the standard-care group. There was no significant difference in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13; P=0.97).

    CONCLUSIONS: When used to target normal fasting plasma glucose levels for more than 6 years, insulin glargine had a neutral effect on cardiovascular outcomes and cancers. Although it reduced new-onset diabetes, insulin glargine also increased hypoglycemia and modestly increased weight. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).

  • 40.
    Gordh, Torsten E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Jensen, Troels S.
    Kalso, Eija
    Reporting of Trials of Gabapentin2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 362, no 17, p. 1641-1641Article in journal (Refereed)
  • 41. Granger, Christopher B.
    et al.
    Alexander, John H.
    McMurray, John J. V.
    Lopes, Renato D.
    Hylek, Elaine M.
    Hanna, Michael
    Al-Khalidi, Hussein R.
    Ansell, Jack
    Atar, Dan
    Avezum, Alvaro
    Cecilia Bahit, M.
    Diaz, Rafael
    Easton, J. Donald
    Ezekowitz, Justin A.
    Flaker, Greg
    Garcia, David
    Geraldes, Margarida
    Gersh, Bernard J.
    Golitsyn, Sergey
    Goto, Shinya
    Hermosillo, Antonio G.
    Hohnloser, Stefan H.
    Horowitz, John
    Mohan, Puneet
    Jansky, Petr
    Lewis, Basil S.
    Luis Lopez-Sendon, Jose
    Pais, Prem
    Parkhomenko, Alexander
    Verheugt, Freek W. A.
    Zhu, Jun
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Apixaban versus Warfarin in Patients with Atrial Fibrillation2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 365, no 11, p. 981-992Article in journal (Refereed)
    Abstract [en]

    Background Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. Methods In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. Results The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). Conclusions In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.

  • 42. Granger, Christopher B.
    et al.
    Hanna, Michael
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Apixaban versus Warfarin in Atrial Fibrillation REPLY2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 366, no 1, p. 89-89Article in journal (Refereed)
  • 43.
    Groopman, Emily E.
    et al.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Marasa, Maddalena
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Cameron-Christie, Sophia
    AstraZeneca Ctr Genom Res Precis Med & Genom, Innovat Med & Early Dev IMED Biotech Uni, Cambridge, England.
    Petrovski, Slavé
    AstraZeneca Ctr Genom Res Precis Med & Genom, Innovat Med & Early Dev IMED Biotech Uni, Cambridge, England.
    Aggarwal, Vimla S.
    Hammer Hlth Sci, Div Nephrol, Dept Pathol, New York, NY USA.
    Milo-Rasouly, Hila
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Li, Yifu
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Zhang, Junying
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Nestor, Jordan
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Krithivasan, Priya
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Lam, Wan Yee
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Mitrotti, Adele
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Piva, Stacy
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Kil, Byum H.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Chatterjee, Debanjana
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Reingold, Rachel
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Bradbury, Drew
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    DiVecchia, Michael
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Snyder, Holly
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Mu, Xueru
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Mehl, Karla
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Balderes, Olivia
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Fasel, David A.
    Hammer Hlth Sci, Dept Biomed Informat, New York, NY USA.
    Weng, Chunhua
    Hammer Hlth Sci, Dept Biomed Informat, New York, NY USA.
    Radhakrishnan, Jai
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Canetta, Pietro
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Appel, Gerald B.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Bomback, Andrew S.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Ahn, Wooin
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Uy, Natalie S.
    Hammer Hlth Sci, Dept Pediat, New York, NY USA.
    Alam, Shumyle
    Hammer Hlth Sci, Dept Urol, New York, NY USA.
    Cohen, David J.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Crew, Russell J.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Dube, Geoffrey K.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Rao, Maya K.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Kamalakaran, Sitharthan
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Copeland, Brett
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Ren, Zhong
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Bridgers, Joshua
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Malone, Colin D.
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Mebane, Caroline M.
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Dagaonkar, Neha
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Fellström, Bengt C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Haefliger, Carolina
    AstraZeneca Ctr Genom Res Precis Med & Genom, Innovat Med & Early Dev IMED Biotech Uni, Cambridge, England.
    Mohan, Sumit
    Hammer Hlth Sci, Dept Med, New York, NY USA;Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA.
    Sanna-Cherchi, Simone
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Kiryluk, Krzysztof
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Fleckner, Jan
    AstraZeneca Ctr Genom Res Precis Med & Genom, Innovat Med & Early Dev IMED Biotech Uni, Cambridge, England.
    March, Ruth
    AstraZeneca Ctr Genom Res Precis Med & Genom, Innovat Med & Early Dev IMED Biotech Uni, Cambridge, England.
    Platt, Adam
    AstraZeneca Ctr Genom Res Precis Med & Genom, Innovat Med & Early Dev IMED Biotech Uni, Cambridge, England.
    Goldstein, David B.
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA;Hammer Hlth Sci, Dept Genet & Dev, New York, NY USA.
    Gharavi, Ali G.
    Hammer Hlth Sci, Dept Med, New York, NY USA;Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Diagnostic Utility of Exome Sequencing for Kidney Disease2019In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 380, no 2, p. 142-151Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally.

    METHODS We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings.

    RESULTS In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management.

    CONCLUSIONS Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases.

  • 44.
    Götberg, M.
    et al.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden..
    Christiansen, E. H.
    Aarhus Univ Hosp, Dept Cardiol, Aarhus, Denmark..
    Gudmundsdottir, I. J.
    Reykjavik Univ Hosp, Dept Cardiol, Reykjavik, Iceland..
    Sandhall, L.
    Helsingborg Hosp, Dept Cardiol & Radiol, Helsingborg, Sweden..
    Danielewicz, M.
    Karlstad Hosp, Dept Cardiol, Karlstad, Sweden..
    Jakobsen, L.
    Aarhus Univ Hosp, Dept Cardiol, Aarhus, Denmark..
    Olsson, S. -E
    Öhagen, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Olsson, H.
    Karlstad Hosp, Dept Cardiol, Karlstad, Sweden..
    Omerovic, E.
    Sahlgrenska Univ, Dept Cardiol, Gothenburg, Sweden..
    Calais, F.
    Orebro Univ, Fac Hlth, Dept Cardiol, Orebro, Sweden..
    Lindroos, P.
    St Goran Hosp, Dept Cardiol, Stockholm, Sweden..
    Maeng, M.
    Aarhus Univ Hosp, Dept Cardiol, Aarhus, Denmark..
    Tödt, T.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden..
    Venetsanos, D.
    Linkoping Univ, Dept Cardiol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Kåregren, A.
    Vastmanland Hosp Vasters, Dept Internal Med, Vasteras, Sweden..
    Nilsson, M.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden..
    Carlsson, J.
    Kalmar Cty Hosp, Dept Cardiol, Kalmar, Sweden.;Linnaeus Univ, Fac Hlth & Life Sci, Kalmar, Sweden..
    Hauer, D.
    Linkoping Univ, Dept Cardiol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Jensen, J.
    Karolinska Inst, Sodersjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.;Capio St Gorans Sjukhus, Unit Cardiol, Stockholm, Sweden.;Sundsvall Hosp, Dept Med, Sundsvall, Sweden..
    Karlsson, A. -C
    Panayi, G.
    Linkoping Univ, Dept Cardiol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Erlinge, D.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden..
    Fröbert, O.
    Orebro Univ, Fac Hlth, Dept Cardiol, Orebro, Sweden..
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 376, no 19, p. 1813-1823Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The instantaneous wave-free ratio (iFR) is an index used to assess the severity of coronary-artery stenosis. The index has been tested against fractional flow reserve (FFR) in small trials, and the two measures have been found to have similar diagnostic accuracy. However, studies of clinical outcomes associated with the use of iFR are lacking. We aimed to evaluate whether iFR is noninferior to FFR with respect to the rate of subsequent major adverse cardiac events.

    METHODS We conducted a multicenter, randomized, controlled, open-label clinical trial using the Swedish Coronary Angiography and Angioplasty Registry for enrollment. A total of 2037 participants with stable angina or an acute coronary syndrome who had an indication for physiologically guided assessment of coronary-artery stenosis were randomly assigned to undergo revascularization guided by either iFR or FFR. The primary end point was the rate of a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization within 12 months after the procedure.

    RESULTS A primary end-point event occurred in 68 of 1012 patients (6.7%) in the iFR group and in 61 of 1007 (6.1%) in the FFR group (difference in event rates, 0.7 percentage points; 95% confidence interval [CI], -1.5 to 2.8; P = 0.007 for noninferiority; hazard ratio, 1.12; 95% CI, 0.79 to 1.58; P = 0.53); the upper limit of the 95% confidence interval for the difference in event rates fell within the prespecified noninferiority margin of 3.2 percentage points. The results were similar among major subgroups. The rates of myocardial infarction, target-lesion revascularization, restenosis, and stent thrombosis did not differ significantly between the two groups. A significantly higher proportion of patients in the FFR group than in the iFR group reported chest discomfort during the procedure.

    CONCLUSIONS Among patients with stable angina or an acute coronary syndrome, an iFR-guided revascularization strategy was noninferior to an FFR-guided revascularization strategy with respect to the rate of major adverse cardiac events at 12 months.

  • 45.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Digoxin for the treatment of heart failure2003In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 348, no 7, p. 661-662Article in journal (Refereed)
  • 46.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Odlind, Viveca
    Medical Products Agency.
    Sjöblom, Viktoria
    Selective serotonin-reuptake inhibitors and persistent pulmonary hypertension of the newborn2006In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 354, no 20, p. 2188-2190Article in journal (Refereed)
  • 47. Hiatt, William R
    et al.
    Fowkes, F Gerry R
    Heizer, Gretchen
    Berger, Jeffrey S
    Baumgartner, Iris
    Held, Peter
    Katona, Brian G
    Mahaffey, Kenneth W
    Norgren, Lars
    Jones, W Schuyler
    Blomster, Juuso
    Millegård, Marcus
    Reist, Craig
    Patel, Manesh R
    Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease.2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 376, no 1, p. 32-40Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease.

    METHODS: In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median follow-up was 30 months.

    RESULTS: The median age of the patients was 66 years, and 72% were men; 43% were enrolled on the basis of the ABI and 57% on the basis of previous revascularization. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49).

    CONCLUSIONS: In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups. (Funded by AstraZeneca; EUCLID ClinicalTrials.gov number, NCT01732822 .).

  • 48.
    Hofmann, Robin
    et al.
    Soder Sjukhuset, Karolinska Inst, Dept Clin Sci & Educ, Div Cardiol, Sjukhusbacken 10, S-11883 Stockholm, Sweden..
    James, Stefan K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Jernberg, Tomas
    Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Cardiol, Stockholm, Sweden..
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Erlinge, David
    Lund Univ, Dept Clin Sci, Cardiol, Lund, Sweden..
    Witt, Nils
    Soder Sjukhuset, Karolinska Inst, Dept Clin Sci & Educ, Div Cardiol, Sjukhusbacken 10, S-11883 Stockholm, Sweden..
    Arefalk, Gabriel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Frick, Mats
    Soder Sjukhuset, Karolinska Inst, Dept Clin Sci & Educ, Div Cardiol, Sjukhusbacken 10, S-11883 Stockholm, Sweden..
    Alfredsson, Joakim
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.;Linkoping Univ, Dept Cardiol, Linkoping, Sweden..
    Nilsson, Lennart
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.;Linkoping Univ, Dept Cardiol, Linkoping, Sweden..
    Ravn-Fischer, Annica
    Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Omerovic, Elmir
    Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Kellerth, Thomas
    Orebro Univ Hosp, Dept Cardiol, Orebro, Sweden..
    Sparv, David
    Lund Univ, Dept Clin Sci, Cardiol, Lund, Sweden..
    Ekelund, Ulf
    Lund Univ, Dept Clin Sci, Emergency Med, Lund, Sweden..
    Linder, Rickard
    Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Cardiol, Stockholm, Sweden..
    Ekstrom, Mattias
    Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Cardiol, Stockholm, Sweden..
    Lauermann, Jorg
    Ryhov Hosp, Dept Internal Med, Div Cardiol, Jonkoping, Sweden..
    Haaga, Urban
    Karlstad Cent Hosp, Dept Cardiol, Karlstad, Sweden..
    Pernow, John
    Karolinska Univ Hosp, Dept Cardiol, Solna, Sweden.;Karolinska Inst, Dept Med, Solna, Sweden..
    Östlund, Ollie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Herlitz, Johan
    Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden.;Univ Boras, Dept Hlth Sci, Boras, Sweden..
    Svensson, Leif
    Soder Sjukhuset, Karolinska Inst, Ctr Resuscitat Sci, Stockholm, Sweden.;Karolinska Inst, Dept Med, Solna, Sweden..
    Oxygen Therapy in Suspected Acute Myocardial Infarction2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 13, p. 1240-1249Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The clinical effect of routine oxygen therapy in patients with suspected acute myocardial infarction who do not have hypoxemia at baseline is uncertain. METHODS In this registry-based randomized clinical trial, we used nationwide Swedish registries for patient enrollment and data collection. Patients with suspected myocardial infarction and an oxygen saturation of 90% or higher were randomly assigned to receive either supplemental oxygen (6 liters per minute for 6 to 12 hours, delivered through an open face mask) or ambient air. RESULTS A total of 6629 patients were enrolled. The median duration of oxygen therapy was 11.6 hours, and the median oxygen saturation at the end of the treatment period was 99% among patients assigned to oxygen and 97% among patients assigned to ambient air. Hypoxemia developed in 62 patients (1.9%) in the oxygen group, as compared with 254 patients (7.7%) in the ambient-air group. The median of the highest troponin level during hospitalization was 946.5 ng per liter in the oxygen group and 983.0 ng per liter in the ambient-air group. The primary end point of death from any cause within 1 year after randomization occurred in 5.0% of patients (166 of 3311) assigned to oxygen and in 5.1% of patients (168 of 3318) assigned to ambient air (hazard ratio, 0.97; 95% confidence interval [CI], 0.79 to 1.21; P = 0.80). Rehospitalization with myocardial infarction within 1 year occurred in 126 patients (3.8%) assigned to oxygen and in 111 patients (3.3%) assigned to ambient air (hazard ratio, 1.13; 95% CI, 0.88 to 1.46; P = 0.33). The results were consistent across all predefined subgroups. CONCLUSIONS Routine use of supplemental oxygen in patients with suspected myocardial infarction who did not have hypoxemia was not found to reduce 1-year all-cause mortality.

  • 49.
    Hofmann, Robin
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Svensson, Leif
    Karolinska Inst, Stockholm, Sweden..
    James, Stefan K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala Univ, Uppsala, Sweden..
    Oxygen Therapy in Suspected Acute Myocardial Infarction REPLY2018In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 378, no 2, p. 201-202Article in journal (Refereed)
  • 50. Hohnloser, Stefan H.
    et al.
    Crijns, Harry J. G. M.
    van Eickels, Martin
    Gaudin, Christophe
    Page, Richard L.
    Torp-Pedersen, Christian
    Connolly, Stuart J.
    Effect of dronedarone on cardiovascular events in atrial fibrillation2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 360, no 7, p. 668-78Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Dronedarone is a new antiarrhythmic drug that is being developed for the treatment of patients with atrial fibrillation. METHODS: We conducted a multicenter trial to evaluate the use of dronedarone in 4628 patients with atrial fibrillation who had additional risk factors for death. Patients were randomly assigned to receive dronedarone, 400 mg twice a day, or placebo. The primary outcome was the first hospitalization due to cardiovascular events or death. Secondary outcomes were death from any cause, death from cardiovascular causes, and hospitalization due to cardiovascular events. RESULTS: The mean follow-up period was 21+/-5 months, with the study drug discontinued prematurely in 696 of the 2301 patients (30.2%) receiving dronedarone and in 716 of the 2327 patients (30.8%) receiving placebo, mostly because of adverse events. The primary outcome occurred in 734 patients (31.9%) in the dronedarone group and in 917 patients (39.4%) in the placebo group, with a hazard ratio for dronedarone of 0.76 (95% confidence interval [CI], 0.69 to 0.84; P<0.001). There were 116 deaths (5.0%) in the dronedarone group and 139 (6.0%) in the placebo group (hazard ratio, 0.84; 95% CI, 0.66 to 1.08; P=0.18). There were 63 deaths from cardiovascular causes (2.7%) in the dronedarone group and 90 (3.9%) in the placebo group (hazard ratio, 0.71; 95% CI, 0.51 to 0.98; P=0.03), largely due to a reduction in the rate of death from arrhythmia with dronedarone. The dronedarone group had higher rates of bradycardia, QT-interval prolongation, nausea, diarrhea, rash, and an increased serum creatinine level than the placebo group. Rates of thyroid- and pulmonary-related adverse events were not significantly different between the two groups. CONCLUSIONS: Dronedarone reduced the incidence of hospitalization due to cardiovascular events or death in patients with atrial fibrillation. (ClinicalTrials.gov number, NCT00174785.)

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