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  • 1. Andersson, RE
    et al.
    Olaison, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Tysk, C
    Ekbom, A
    Appendectomy and protection against ulcerative colitis2001In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 344, no 11, p. 808-814Article in journal (Refereed)
    Abstract [en]

    Background: A history of appendectomy is rare in patients with ulcerative colitis. This suggests a protective effect of appendectomy or that appendicitis and ulcerative colitis are alternative inflammatory responses. We sought to characterize this inverse relation further. Methods:We studied a cohort of 212,963 patients who underwent appendectomy before the age of 50 years between 1964 and 1993 and a cohort of matched controls who were identified from the Swedish Inpatient Register and the nationwide census. The cohort was followed until 1995 for any subsequent diagnosis of ulcerative colitis. Results: Patients who underwent appendectomy for appendicitis and mesenteric lymphadenitis had a low risk of ulcerative colitis (for patients with perforated appendicitis, the adjusted hazard ratio was 0.58 [95 percent confidence interval, 0.38 to 0.87], for those with nonperforated appendicitis it was 0.76 [95 percent confidence interval, 0.65 to 0.90], and for those with mesenteric lymphadenitis it was 0.57 [95 percent confidence interval, 0.36 to 0.89]). In contrast, patients who underwent appendectomy for nonspecific abdominal pain had the same risk of ulcerative colitis as the controls (adjusted hazard ratio, 1.06, 95 percent confidence interval, 0.74 to 1.52). For the patients who had appendicitis, an inverse relation with the risk of ulcerative colitis was found only for those who underwent surgery before the age of 20 years (P<0.001). Conclusions: Appendectomy for an inflammatory condition (appendicitis or lymphadenitis) but not for nonspecific abdominal pain is associated with a low risk of subsequent ulcerative colitis. This inverse relation is limited to patients who undergo surgery before the age of 20 years.

  • 2.
    Aspelin, P
    et al.
    Huddinge University Hospital.
    Aubry, P
    Centre Hospitalier Universitaire Bichat.
    Fransson, Sven Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Radiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Strasser, R
    Technische Universität, Dresden.
    Willenbrock, R
    Helios Kliniken, Berlin.
    Berg, K
    Rikshospitalet, Oslo.
    Nephrotoxic effects in high-risk patients undergoing angiography2003In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 348, no 6, p. 491-499Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The use of iodinated contrast medium can result in nephropathy. Whether iso-osmolar contrast medium is less nephrotoxic than low-osmolar contrast medium in high-risk patients is uncertain. METHODS: We conducted a randomized, double-blind, prospective, multicenter study comparing the nephrotoxic effects of an iso-osmolar, dimeric, nonionic contrast medium, iodixanol, with those of a low-osmolar, nonionic, monomeric contrast medium, iohexol. The study involved 129 patients with diabetes with serum creatinine concentrations of 1.5 to 3.5 mg per deciliter who underwent coronary or aortofemoral angiography. The primary end point was the peak increase from base line in the creatinine concentration during the three days after angiography. Other end points were an increase in the creatinine concentration of 0.5 mg per deciliter or more, an increase of 1.0 mg per deciliter or more, and a change in the creatinine concentration from day 0 to day 7. RESULTS: The creatinine concentration increased significantly less in patients who received iodixanol. From day 0 to day 3, the mean peak increase in creatinine was 0.13 mg per deciliter in the iodixanol group and 0.55 mg per deciliter in the iohexol group (P=0.001, the increase with iodixanol minus the increase with iohexol, -0.42 mg per deciliter [95 percent confidence interval, -0.73 to -0.22]). Two of the 64 patients in the iodixanol group (3 percent) had an increase in the creatinine concentration of 0.5 mg per deciliter or more, as compared with 17 of the 65 patients in the iohexol group (26 percent) (P=0.002, odds ratio for such an increase in the iodixanol group, 0.09 [95 percent confidence interval, 0.02 to 0.41]). No patient receiving iodixanol had an increase of 1.0 mg per deciliter or more, but 10 patients in the iohexol group (15 percent) did. The mean change in the creatinine concentration from day 0 to day 7 was 0.07 mg per deciliter in the iodixanol group and 0.24 mg per deciliter in the iohexol group (P=0.003, value in the iodixanol group minus the value in the iohexol group, -0.17 mg per deciliter [95 percent confidence interval, -0.34 to -0.07]). CONCLUSIONS: Nephropathy induced by contrast medium may be less likely to develop in high-risk patients when iodixanol is used rather than a low-osmolar, nonionic contrast medium.

  • 3.
    Barnett, A.H.
    et al.
    Division of Medical Sciences, University of Birmingham, Birmingham Heartlands Solihull N., Birmingham, United Kingdom, Undergraduate Center, Birmingham Heartlands Hospital, Bordesley Green E., Birmingham B9 5SS, United Kingdom.
    Bain, S.C.
    Division of Medical Sciences, University of Birmingham, Birmingham Heartlands Solihull N., Birmingham, United Kingdom.
    Bouter, P.
    Department of Internal Medicine, Bosch Medicentre, Den Bosch, Netherlands.
    Karlberg, B.
    Östergötlands Läns Landsting.
    Madsbad, S.
    Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.
    Jervell, J.
    University Hospital of Oslo, Oslo, Norway.
    Mustonen, J.
    Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.
    Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy2004In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 351, no 19, p. 1952-1961Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Few studies have directly compared the renoprotective effects of angiotensin II-receptor blockers and angiotensin-converting-enzyme (ACE) inhibitors in persons with type 2 diabetes. METHODS: In this prospective, multicenter, double-blind, five-year study, we randomly assigned 250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin II-receptor blocker telmisartan (80 mg daily, in 120 subjects) or the ACE inhibitor enalapril (20 mg daily, in 130 subjects). The primary end point was the change in the glomerular filtration rate (determined by measuring the plasma clearance of iohexol) between the baseline value and the last available value during the five-year treatment period. Secondary end points included the annual changes in the glomerular filtration rate, serum creatinine level, urinary albumin excretion, and blood pressure, the rates of end-stage renal disease and cardiovascular events, and the rate of death from all causes. RESULTS: After five years, the change in the glomerular filtration rate was -17.9 ml per minute per 1.73 m2 of body-surface area, where the minus sign denotes a decrement, with telmisartan (in 103 subjects), as compared with -14.9 ml per minute per 1.73 m2 with enalapril (in 113 subjects), for a treatment difference of -3.0 ml per minute per 1.73 m2 (95 percent confidence interval, -7.6 to 1.6 ml per minute per 1.73 m2). The lower boundary of the confidence interval, in favor of enalapril, was greater than the pre-defined margin of -10.0 ml per minute per 1.73 m2, indicating that telmisartan was not inferior to enalapril. The effects of the two agents on the secondary end points were not significantly different after five years. CONCLUSIONS: Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with type 2 diabetes. These findings do not necessarily apply to persons with more advanced nephropathy, but they support the clinical equivalence of angiotensin II-receptor blockers and ACE inhibitors in persons with conditions that place them at high risk for cardiovascular events. Copyright © 2004 Massachusetts Medical Society.

  • 4.
    Bergmark, Karin
    et al.
    Divisions of Gynecological Oncology and Clinical Epidemiology, Department of Oncology, Radiumhemmet, Karolinska Institute, Stockholm, Sweden.
    Åvall-Lundqvist, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Division of Gynecological Oncology Department of Oncology, Radiumhemmet, Karolinska Institute, Stockholm, Sweden.
    Dickman, Paul W
    Division of Clinical Epidemiology, Department of Oncology, Radiumhemmet, Karolinska Institute, Stockholm, Sweden.
    Henningsohn, Lars
    Division of Clinical Epidemiology, Department of Oncology, Radiumhemmet, Karolinska Institute, Stockholm, Sweden.
    Steineck, Gunar
    Division of Clinical Epidemiology, Department of Oncology, Radiumhemmet, Karolinska Institute, Stockholm, Sweden.
    Vaginal changes and sexuality in women with a history of cervical cancer.1999In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 340, no 18, p. 1383-1389Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In women with cervical cancer, treatment causes changes in vaginal anatomy and function. The effect of these changes on sexual function and the extent, if any, to which they distress women are not known.

    METHODS: In 1996 and 1997, we attempted to contact 332 women with a history of early-stage cervical cancer (age range, 26 to 80 years) who had been treated in 1991 and 1992 at the seven departments of gynecological oncology in Sweden and 489 women without a history of cancer (controls) to ask them to answer an anonymous questionnaire about vaginal changes and sexual function.

    RESULTS: We received completed questionnaires from 256 of the women with a history of cervical cancer and 350 of the controls. A total of 167 of 247 women with a history of cancer (68 percent) and 236 of 330 controls (72 percent) reported that they had regular vaginal intercourse. Twenty-six percent of the women who had cancer and 11 percent of the controls reported insufficient vaginal lubrication for sexual intercourse, 26 percent of the women who had cancer and 3 percent of the controls reported a short vagina, and 23 percent of the women who had cancer and 4 percent of the controls reported an insufficiently elastic vagina. Twenty-six percent of the women who had cancer reported moderate or much distress due to vaginal changes, as compared with 8 percent of the women in the control group. Dyspareunia was also more common among the women who had cervical cancer. The frequency of orgasms and orgasmic pleasure was similar in the two groups. Among the women who had cervical cancer, the type of treatment received had little if any effect on the prevalence of specific vaginal changes.

    CONCLUSIONS: Women who have been treated for cervical cancer have persistent vaginal changes that compromise sexual activity and result in considerable distress.

  • 5.
    Bill-Axelson, A.
    et al.
    Department of Urology, University Hospital, Uppsala, Sweden, Department of Urology, University Hospital, SE-751 85 Uppsala, Sweden.
    Holmberg, L.
    Regional Oncologic Center, University Hospital, Uppsala, Sweden.
    Ruutu, M.
    Depatment of Urology, University of Helsinki, University Hospital of Helsinki, Helsinki, Finland.
    Haggman, M.
    Häggman, M., Department of Urology, University Hospital, Uppsala, Sweden.
    Andersson, S.-O.
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Bratell, S.
    Department of Urology, Boras Hospital, Boras, Sweden.
    Spångberg, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Urology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Busch, C.
    Department of Pathology, University Hospital, Uppsala, Sweden.
    Nordling, S.
    Department of Pathology, University of Helsinki, University Hospital of Helsinki, Helsinki, Finland.
    Garmo, H.
    Regional Oncologic Center, University Hospital, Uppsala, Sweden.
    Palmgren, J.
    Dept. Med. Epidemiol. Biostatist., Karolinska Institutet, Stockholm, Sweden.
    Adami, H.-O.
    Dept. Med. Epidemiol. Biostatist., Karolinska Institutet, Stockholm, Sweden, Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States.
    Norlen, B.J.
    Norlén, B.J., Department of Urology, University Hospital, Uppsala, Sweden.
    Johansson, J.-E.
    Department of Urology, Örebro University Hospital, Örebro, Sweden, Ctr. for Assess. of Med. Technology, Örebro University Hospital, Örebro, Sweden.
    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. 1977-1984Article 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. Copyright © 2005 Massachusetts Medical Society.

  • 6.
    Bill-Axelson, Anna
    et al.
    University of Uppsala Hospital, Sweden .
    Holmberg, Lars
    University of Uppsala Hospital, Sweden Kings Coll London, England .
    Garmo, Hans
    University of Uppsala Hospital, Sweden Kings Coll London, England .
    Rider, Jennifer R.
    Brigham and Womens Hospital, MA USA Harvard University, MA USA Harvard University, MA 02115 USA .
    Taari, Kimmo
    University of Helsinki, Finland .
    Busch, Christer
    University of Uppsala Hospital, Sweden .
    Nordling, Stig
    University of Helsinki, Finland .
    Haggman, Michael
    University of Uppsala Hospital, Sweden .
    Andersson, Swen-Olof
    University of Örebro, Sweden Örebro University Hospital, Sweden .
    Spångberg, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Andren, Ove
    University of Örebro, Sweden Örebro University Hospital, Sweden .
    Palmgren, Juni
    Karolinska Institute, Sweden .
    Steineck, Gunnar
    Karolinska Institute, Sweden Sahlgrens Acad, Sweden .
    Adami, Hans-Olov
    Karolinska Institute, Sweden Harvard University, MA 02115 USA .
    Johansson, Jan-Erik
    University of Örebro, Sweden Örebro University Hospital, Sweden .
    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 ...

  • 7.
    Cannon, Christopher P.
    et al.
    Baim Institute for Clinical Research, USA; Brigham and Women’s Hospital, Heart and Vascular Center, USA; Harvard Medical School, USA.
    Bhatt, Deepak L.
    Brigham and Women’s Hospital, Heart and Vascular Center, USA; Harvard Medical School, USA.
    Oldgren, Jonas
    Uppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Lip, Gregory Y. H.
    Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.
    Ellis, Stephen G.
    Cleveland Clinic, Cleveland, USA.
    Kimura, Takeshi
    Kyoto University, Department of Cardiovascular Medicine, Kyoto, Japan.
    Maeng, Michael
    Aarhus University Hospital, Skejby, Denmark.
    Merkely, Bela
    University Heart and Vascular Center, Budapest, Hungary.
    Zeymer, Uwe
    Klinikum der Stadt Ludwigshafen am Rhein, Medizinische Klinik B, Ludwigshafen, Germany.
    Gropper, Savion
    Boehringer Ingelheim, Ingelheim, Germany.
    Nordaby, Matias
    Boehringer Ingelheim, Ingelheim, Germany.
    Kleine, Eva
    Boehringer Ingelheim, Ingelheim, Germany.
    Harper, Ruth
    Boehringer Ingelheim, Bracknell, UK.
    Manassie, Jenny
    Boehringer Ingelheim, Bracknell, UK.
    Januzzi, James L.
    Baim Institute for Clinical Research, USA; Cardiology Division, Massachusetts General Hospital, USA; Harvard Medical School, USA.
    Ten Berg, Jurrien M.
    St. Antonius Ziekenhuis, Nieuwegein, Netherlands.
    Steg, P. Gabriel
    Imperial College, London, London, UK.
    Hohnloser, Stefan H.
    Johann Wolfgang Goethe University, Department of Medicine, Division of Cardiology, Frankfurt am Main, Germany.
    Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation.2017In: 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: 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: inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events. (Funded by Boehringer Ingelheim; RE-DUAL PCI ClinicalTrials.gov number, NCT02164864)

  • 8.
    Cosedis Nielsen, Jens
    et al.
    Aarhus University Hospital, Denmark.
    Johannessen, Arne
    Gentofte University Hospital, Copenhagen, Denmark.
    Raatikainen, Pekka
    Tampere University Hospital, Finland.
    Hindricks, Gerhard
    Leipzig University Hospital, Germany.
    Walfridsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Kongstad, Ole
    Lund University Hospital, Sweden.
    Pehrson, Steen
    Rigshospitalet, Copenhagen, Denmark.
    Englund, Anders
    University Hospital Örebro, Sweden.
    Hartikainen, Juha
    Kuopio University Hospital, Finland.
    Spange Mortensen, Leif
    UNI-C, Danish Information Technology Center for Education and Research, Aarhus, Denmark.
    Steen Hansen, Peter
    Aarhus University Hospital, Denmark.
    Radiofrequency Ablation as Initial Therapy in Paroxysm Atrial Fibrillation2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 17, p. 1587-1595Article in journal (Refereed)
    Abstract [en]

    Background

    There are limited data comparing radiofrequency catheter ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation.

    Methods

    We randomly assigned 294 patients with paroxysmal atrial fibrillation and no history of antiarrhythmic drug use to an initial treatment strategy of either radiofrequency catheter ablation (146 patients) or therapy with class IC or class III antiarrhythmic agents (148 patients). Follow-up included 7-day Holter-monitor recording at 3, 6, 12, 18, and 24 months. Primary end points were the cumulative and per-visit burden of atrial fibrillation (i.e., percentage of time in atrial fibrillation on Holter-monitor recordings). Analyses were performed on an intention-to-treat basis.

    Results

    There was no significant difference between the ablation and drug-therapy groups in the cumulative burden of atrial fibrillation (90th percentile of arrhythmia burden, 13% and 19%, respectively; P=0.10) or the burden at 3, 6, 12, or 18 months. At 24 months, the burden of atrial fibrillation was significantly lower in the ablation group than in the drug-therapy group (90th percentile, 9% vs. 18%; P=0.007), and more patients in the ablation group were free from any atrial fibrillation (85% vs. 71%, P=0.004) and from symptomatic atrial fibrillation (93% vs. 84%, P=0.01). One death in the ablation group was due to a procedure-related stroke; there were three cases of cardiac tamponade in the ablation group. In the drug-therapy group, 54 patients (36%) underwent supplementary ablation.

    Conclusions

    In comparing radiofrequency ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation, we found no significant difference between the treatment groups in the cumulative burden of atrial fibrillation over a period of 2 years.

  • 9.
    Erlinge, D.
    et al.
    Lund University, Sweden.
    Omerovic, E.
    Sahlgrens University Hospital, Sweden.
    Frobert, O.
    Örebro University, Sweden.
    Linder, R.
    Danderyd Hospital, Sweden.
    Danielewicz, M.
    Karlstad Hospital, Sweden.
    Hamid, M.
    Mälarsjukhuset, Sweden.
    Swahn, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Henareh, L.
    Karolinska University Hospital, Sweden.
    Wagner, H.
    Helsingborg Lasarett, Sweden.
    Hardhammar, P.
    Halmstad County Hospital, Sweden.
    Sjogren, I.
    Falun Central Hospital, Sweden.
    Stewart, J.
    Skaraborgs Hospital, Sweden.
    Grimfjard, P.
    Västmanlands Sjukhus, Sweden.
    Jensen, J.
    Karolinska Institute, Sweden.
    Aasa, M.
    Södersjukhuset AB, Sweden.
    Robertsson, L.
    Södra Älvsborgs Sjukhus, Sweden.
    Lindroos, P.
    Karolinska Institute, Sweden.
    Haupt, J.
    Sunderby Sjukhus, Sweden.
    Wikstrom, H.
    Kristianstad Hospital, Sweden.
    Ulvenstam, A.
    Östersund Hospital, Sweden.
    Bhiladvala, P.
    Lund University, Sweden.
    Lindvall, B.
    Sundsvall Hospital, Sweden.
    Lundin, A.
    Lund University, Sweden.
    Todt, T.
    Lund University, Sweden.
    Ioanes, D.
    Sahlgrens University Hospital, Sweden.
    Ramunddal, T.
    Sahlgrens University Hospital, Sweden.
    Kellerth, T.
    Örebro University, Sweden.
    Zagozdzon, L.
    Örebro University, Sweden.
    Gotberg, M.
    Lund University, Sweden.
    Andersson, J.
    Umeå University, Sweden.
    Angeras, O.
    Sahlgrens University Hospital, Sweden.
    Ostlund, O.
    Uppsala University, Sweden.
    Lagerqvist, B.
    Uppsala University, Sweden.
    Held, C.
    Uppsala University, Sweden.
    Wallentin, L.
    Uppsala University, Sweden.
    Schersten, F.
    Lund University, Sweden.
    Eriksson, P.
    Umeå University, Sweden.
    Koul, S.
    Lund University, Sweden.
    James, S.
    Uppsala University, Sweden.
    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;

  • 10.
    Galiè, Nazzareno
    et al.
    University of Bologna, Italy.
    Barberà, Joan A
    University of Barcelona and Biomedical Research Networking Center on Respiratory Diseases, Madrid, Spain.
    Frost, Adaani E
    Baylor College of Medicine, Houston, USA.
    Ghofrani, Hossein-Ardeschir
    University of Giessen and Marbury Lung Center, Giessen, Germany.
    Hoeper, Marius M
    Hanover Medical School and German Center of Lung Research, Hanover, Germany.
    McLaughlin, Vallerie V
    University of Michigan, USA.
    Peacock, Andrew J
    Regional Heart and Lung Center, Glasgow, Scotland.
    Simonneau, Gérald
    University Paris-Sud, Paris, France.
    Vachiery, Jean-Luc
    Hospital Erasme, Brussels, Belgium.
    Grünig, Ekkehard
    University Hospital Heidelberg, Heidelberg, Germany.
    Oudiz, Ronald J
    UCLA Medical Center, Torrance,USA.
    Vonk-Noordegraaf, Anton
    University Medical Center, Amsterdam, Netherlands.
    White, R James
    University of Rochester, NY, USA.
    Blair, Christiana
    Gilead Sciences, Foster City.
    Gillies, Hunter
    Gilead Sciences, Foster City.
    Miller, Karen L
    Gilead Sciences, Foster City.
    Harris, Julia H N
    GlaxoSmith Kline, Uxbridge, UK.
    Langley, Jonathan
    GlaxoSmith Kline, Uxbridge, UK.
    Rubin, Lewis J
    University of California at San Diego, USA.
    Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension2015In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 373, no 9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce.

    METHODS: In this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan-monotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.

    RESULTS: The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooled-monotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, -67.2% vs. -50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P=0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia.

    CONCLUSIONS: Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.).

  • 11.
    Gotberg, M.
    et al.
    Lund University, Sweden.
    Christiansen, E. H.
    Aarhus University Hospital, Denmark.
    Gudmundsdottir, I. J.
    Reykjavik University Hospital, Iceland.
    Sandhall, L.
    Helsingborg Hospital, Sweden.
    Danielewicz, M.
    Karlstad Hospital, Sweden.
    Jakobsen, L.
    Aarhus University Hospital, Denmark.
    Olsson, S. -E.
    Helsingborg Hospital, Sweden.
    Ohagen, P.
    Uppsala University, Sweden.
    Olsson, H.
    Karlstad Hospital, Sweden.
    Omerovic, E.
    Sahlgrenska University, Sweden.
    Calais, F.
    Örebro University, Sweden.
    Lindroos, P.
    St Goran Hospital, Sweden.
    Maeng, M.
    Aarhus University Hospital, Denmark.
    Todt, T.
    Lund University, Sweden.
    Venetsanos, Dimitrios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    James, S. K.
    Uppsala University, Sweden.
    Karegren, A.
    Västmanland Hospital Västerås, Sweden.
    Nilsson, M.
    Lund University, Sweden.
    Carlsson, J.
    Kalmar County Hospital, Sweden; Linnaeus University, Sweden.
    Hauer, D.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Jensen, J.
    Karolinska Institute, Sweden; Capio St Gorans Sjukhus, Sweden; Sundsvall Hospital, Sweden.
    Karlsson, A. -C.
    Halmstad County Hospital, Sweden.
    Panayi, G.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Erlinge, D.
    Lund University, Sweden.
    Frobert, O.
    Örebro University, Sweden.
    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.

  • 12.
    Guigliano, Robert P
    et al.
    Women's Hospital, Boston.
    White, Jennifer A
    Duke University Medical Center, Durham.
    Bode, Christoph
    Universitätsklinikum Freiburg.
    Armstrong, Paul W
    University of Alberta, Edmonton, Canada .
    Montalescot, Gilles
    Centre Hospitalier Universitaire Pitié–Salpêtrière, Paris .
    Lewis, Basil S
    Lady Davis Carmel Medical Center, Haifa, Israel.
    van't Hof, Arnoud
    Isala Klinieken, Zwolle, the Netherlands .
    Berdan, Lisa G
    Duke University Medical Center, Durham.
    Lee, Kerry L
    Duke University Medical Center, Durham.
    Strony, John T
    Schering-Plough, Kenilworth.
    Hildemann, Steven
    Essex-Pharma, Munich.
    Veltri, Enrico
    Schering-Plough, Kenilworth.
    Van de Werf, Frans
    Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium.
    Braunwald, Eugene
    Women's Hospital, Boston.
    Harrington, Robert A
    Duke University Medical Center, Durham.
    Califf, Robert M
    Duke University Medical Center, Durham.
    Newby, L Kristin
    Duke University Medical Center, Durham.
    Early versus delayed, provisional eptifibatide in acute coronary syndromes.2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 360, no 21, p. 2176-2190Article in journal (Refereed)
    Abstract [en]

    Background Glycoprotein IIb/IIIa inhibitors are indicated in patients with acute coronary syndromes who are undergoing an invasive procedure. The optimal timing of the initiation of such therapy is unknown.

    Methods We compared a strategy of early, routine administration of eptifibatide with delayed, provisional administration in 9492 patients who had acute coronary syndromes without ST-segment elevation and who were assigned to an invasive strategy. Patients were randomly assigned to receive either early eptifibatide (two boluses, each containing 180 µg per kilogram of body weight, administered 10 minutes apart, and a standard infusion 12 hours before angiography) or a matching placebo infusion with provisional use of eptifibatide after angiography (delayed eptifibatide). The primary efficacy end point was a composite of death, myocardial infarction, recurrent ischemia requiring urgent revascularization, or the occurrence of a thrombotic complication during percutaneous coronary intervention that required bolus therapy opposite to the initial study-group assignment ("thrombotic bailout") at 96 hours. The key secondary end point was a composite of death or myocardial infarction within the first 30 days. Key safety end points were bleeding and the need for transfusion within the first 120 hours after randomization.

    Results The primary end point occurred in 9.3% of patients in the early-eptifibatide group and in 10.0% in the delayed-eptifibatide group (odds ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.23). At 30 days, the rate of death or myocardial infarction was 11.2% in the early-eptifibatide group, as compared with 12.3% in the delayed-eptifibatide group (odds ratio, 0.89; 95% CI, 0.79 to 1.01; P=0.08). Patients in the early-eptifibatide group had significantly higher rates of bleeding and red-cell transfusion. There was no significant difference between the two groups in rates of severe bleeding or nonhemorrhagic serious adverse events.

    Conclusions In patients who had acute coronary syndromes without ST-segment elevation, the use of eptifibatide 12 hours or more before angiography was not superior to the provisional use of eptifibatide after angiography. The early use of eptifibatide was associated with an increased risk of non–life-threatening bleeding and need for transfusion.

     

     

  • 13.
    Hofmann, Robin
    et al.
    Södersjukhuset, Sweden.
    James, Stefan K.
    Uppsala University, Sweden.
    Jernberg, Tomas
    Danderyd Hospital, Sweden.
    Lindahl, Bertil
    Uppsala University, Sweden.
    Erlinge, David
    Lund University, Sweden.
    Witt, Nils
    Södersjukhuset, Sweden.
    Arefalk, Gabriel
    Uppsala University, Sweden.
    Frick, Mats
    Södersjukhuset, Sweden.
    Alfredsson, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Nilsson, Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Ravn-Fischer, Annica
    Sahlgrens University Hospital, Sweden.
    Omerovic, Elmir
    Sahlgrens University Hospital, Sweden.
    Kellerth, Thomas
    Örebro University Hospital, Sweden.
    Sparv, David
    Lund University, Sweden.
    Ekelund, Ulf
    Lund University, Sweden.
    Linder, Rickard
    Danderyd Hospital, Sweden.
    Ekstrom, Mattias
    Danderyd Hospital, Sweden.
    Lauermann, Jorg
    Ryhov Hospital, Sweden.
    Haaga, Urban
    Karlstad Central Hospital, Sweden.
    Pernow, John
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Ostlund, Ollie
    Uppsala University, Sweden.
    Herlitz, Johan
    Sahlgrens University Hospital, Sweden; University of Boras, Sweden.
    Svensson, Leif
    Södersjukhuset, Sweden; Karolinska Institute, 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.

  • 14. Holmberg, Lars
    et al.
    Bill-Axelson, Anna
    Helgesen, Fred
    Salo, Jaakko
    Folmerz, Per
    Häggman, Michael
    Andersson, Swen-Olof
    Spångberg, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Busch, Christer
    Nordling, Steg
    Palmgren, Juni
    Adami, Hans-Olov
    Johansson, Jan-Erik
    Norlén, Bo Johan
    A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer2002In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 347, no 11, p. 781-789Article in journal (Refereed)
    Abstract [en]

    Background: Radical prostatectomy is widely used in the treatment of early prostate cancer. The possible survival benefit of this treatment, however, is unclear. We conducted a randomized trial to address this question. Methods: From October 1989 through February 1999, 695 men with newly diagnosed prostate cancer in International Union against Cancer clinical stage T1b, T1c, or T2 were randomly assigned to watchful waiting or radical prostatectomy. We achieved complete follow-up through the year 2000 with blinded evaluation of causes of death. The primary end point was death due to prostate cancer, and the secondary end points were overall mortality, metastasis-free survival, and local progression. Results: During a median of 6.2 years of follow-up, 62 men in the watchful-waiting group and 53 in the radical-prostatectomy group died (P=0.31). Death due to prostate cancer occurred in 31 of 348 of those assigned to watchful waiting (8.9 percent) and in 16 of 347 of those assigned to radical prostatectomy (4.6 percent) (relative hazard, 0.50, 95 percent confidence interval, 0.27 to 0.91, P=0.02). Death due to other causes occurred in 31 of 348 men in the watchful-waiting group (8.9 percent) and in 37 of 347 men in the radical-prostatectomy group (10.6 percent). The men assigned to surgery had a lower relative risk of distant metastases than the men assigned to watchful waiting (relative hazard, 0.63, 95 percent confidence interval, 0.41 to 0.96). Conclusions: In this randomized trial, radical prostatectomy significantly reduced disease-specific mortality, but there was no significant difference between surgery and watchful waiting in terms of overall survival. Copyright ⌐ 2002 Massachusetts Medical Society.

  • 15.
    Jones, Rachel B.
    et al.
    Vasculitis and Lupus Clinic, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK.
    Tervaer, Jan Willem Cohen
    Division of Clinical and Experimental Immunology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands .
    Hauser, Thomas
    ImmunologieZentrum Zürich and University Hospital, Zurich, Switzerland .
    Luqmani, Raashid
    Department of Rheumatology, Nuffield Orthopaedic Centre, Oxford , UK.
    Morgan, Matthew D.
    Department of Renal Immunobiolo - gy, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
    Peh, Chen Au
    Renal Unit, Royal Adelaide Hospital, Adelaide, Australia .
    Savage, Caroline O.
    Department of Renal Immunobiolo - gy, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology. Department of Nephrology in Lund, University Hospital of Skane and Lund University, Lund, Sweden.
    Tesar, Vladimir
    First Faculty of Medicine, Charles University, Prague, Czech Republic.
    Paassen, Pieter van
    Division of Clinical and Experimental Immunology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
    Wals, Dorothy
    Vasculitis and Lupus Clinic, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK.
    Walsh, Michael
    Vasculitis and Lupus Clinic, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK.
    Westman, Kerstin
    Department of Nephrology and Transplantation in Malmö, University Hospital of Skane and Lund University, Malmö, Sweden.
    Jayne, David R.W.
    Vasculitis and Lupus Clinic, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK.
    Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 363, no 3, p. 211-220Article in journal (Refereed)
    Abstract [en]

    Background

    Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens.

    Methods

    We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events.

    Results

    The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m2 of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14).

    Conclusions

    A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events.

  • 16.
    Lagerqvist, Bo
    et al.
    Uppsala University, Sweden.
    Frobert, Ole
    Örebro University Hospital, Sweden.
    Olivecrona, Goran K.
    Skane University Hospital, Lund University, Sweden.
    Gudnason, Thorarinn
    Landspitali University Hospital, Iceland.
    Maeng, Michael
    Aarhus University Hospital, Denmark.
    Alstrom, Patrik
    Karolinska Institute, Sweden.
    Andersson, Jonas
    Umeå University Hospital, Sweden.
    Calais, Fredrik
    Örebro University Hospital, Sweden.
    Carlsson, Jorg
    Kalmar County Hospital, Sweden; Linnaeus University, Sweden.
    Collste, Olov
    Karolinska Institute, Sweden.
    Gotberg, Matthias
    Skane University Hospital, Lund University, Sweden.
    Hardhammar, Peter
    Halmstad County Hospital, Sweden.
    Ioanes, Dan
    Sahlgrenska University Hospital, Sweden.
    Kallryd, Anders
    Skaraborgs Hospital, Sweden.
    Linder, Rickard
    Karolinska Institute, Sweden.
    Lundin, Anders
    Skane University Hospital, Lund University, Sweden.
    Odenstedt, Jacob
    Sahlgrenska University Hospital, Sweden.
    Omerovic, Elmir
    Sahlgrenska University Hospital, Sweden.
    Puskar, Verner
    Ryhov Hospital, Sweden.
    Tödt, Tim
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Zelleroth, Eva
    Malarsjukhuset, Sweden.
    Ostlund, Ollie
    Uppsala University, Sweden.
    James, Stefan K.
    Uppsala University, Sweden.
    Outcomes 1 Year after Thrombus Aspiration for Myocardial Infarction2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 12, p. 1111-1120Article in journal (Refereed)
    Abstract [en]

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

  • 17.
    Lagerqvist, Bo
    et al.
    Uppsala University Hospital, Sweden.
    James, Stefan K.
    Uppsala University Hospital, Sweden.
    Stenestrand, Ulf
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Lindbäck, Johan
    Uppsala University Hospital, Sweden.
    Nilsson, Tage
    Uppsala University Hospital, Sweden.
    Wallentin, Lars
    Uppsala University Hospital, Sweden.
    Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden2007In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 356, no 10, p. 1009-1019Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recent reports have indicated that there may be an increased risk of late stent thrombosis with the use of drug-eluting stents, as compared with bare-metal stents.

    METHODS: We evaluated 6033 patients treated with drug-eluting stents and 13,738 patients treated with bare-metal stents in 2003 and 2004, using data from the Swedish Coronary Angiography and Angioplasty Registry. The outcome analysis covering a period of up to 3 years was based on 1424 deaths and 2463 myocardial infarctions and was adjusted for differences in baseline characteristics.

    RESULTS: The two study groups did not differ significantly in the composite of death and myocardial infarction during 3 years of follow-up. At 6 months, there was a trend toward a lower unadjusted event rate in patients with drug-eluting stents than in those with bare-metal stents, with 13.4 fewer such events per 1000 patients. However, after 6 months, patients with drug-eluting stents had a significantly higher event rate, with 12.7 more events per 1000 patients per year (adjusted relative risk, 1.20, 95% confidence interval [CI], 1.05 to 1.37). At 3 years, mortality was significantly higher in patients with drug-eluting stents (adjusted relative risk, 1.18, 95% CI, 1.04 to 1.35), and from 6 months to 3 years, the adjusted relative risk for death in this group was 1.32 (95% CI, 1.11 to 1.57).

    CONCLUSIONS: Drug-eluting stents were associated with an increased rate of death, as compared with bare-metal stents. This trend appeared after 6 months, when the risk of death was 0.5 percentage point higher and a composite of death or myocardial infarction was 0.5 to 1.0 percentage point higher per year. The long-term safety of drug-eluting stents needs to be ascertained in large, randomized trials.

  • 18.
    Ludvigsson, Johnny
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Faresjö, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Hjorth, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Axelsson, Stina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Chéramy, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Pihl, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Forsander, Gun
    Ivarsson, Sten
    Johansson, Calle
    Lindh, Agne
    Nilsson, NO
    Åman, Jan
    Örtqvist, Eva
    Zerhouni, Peter
    Casas, Rosaura
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    GAD treatment and insulin secretion in recent-onset type 1 diabetes2008In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 359, no 18, p. 1909-1920Article in journal (Refereed)
    Abstract [en]

    Background: The 65-kD isoform of glutamic acid decarboxylase (GAD) is a major autoantigen in patients with type 1 diabetes mellitus. This trial assessed the ability of alum-formulated GAD (GAD-alum) to reverse recent-onset type 1 diabetes in patients 10 to 18 years of age. Methods: We randomly assigned 70 patients with type 1 diabetes who had fasting C-peptide levels above 0.1 nmol per liter (0.3 ng per milliliter) and GAD autoantibodies, recruited within 18 months after receiving the diagnosis of diabetes, to receive subcutaneous injections of 20 μg of GAD-alum (35 patients) or placebo (alum alone, 35 patients) on study days 1 and 30. At day 1 and months 3, 9, 15, 21, and 30, patients underwent a mixed-meal tolerance test to stimulate residual insulin secretion (measured as the C-peptide level). The effect of GAD-alum on the immune system was also studied. Results: Insulin secretion gradually decreased in both study groups. The study treatment had no significant effect on change in fasting C-peptide level after 15 months (the primary end point). Fasting C-peptide levels declined from baseline levels significantly less over 30 months in the GAD-alum group than in the placebo group (-0.21 vs. -0.27 nmol per liter [-0.62 vs. -0.81 ng per milliliter], P = 0.045), as did stimulated secretion measured as the area under the curve (-0.72 vs. -1.02 nmol per liter per 2 hours [-2.20 vs. -3.08 ng per milliliter per 2 hours], P = 0.04). No protective effect was seen in patients treated 6 months or more after receiving the diagnosis. Adverse events appeared to be mild and similar in frequency between the two groups. The GAD-alum treatment induced a GAD-specific immune response. Conclusions: GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement. (ClinicalTrials.gov number, NCT00435981.) Copyright © 2008 Massachusetts Medical Society. All rights reserved.

  • 19.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Krisky, David
    Diamyd Medical, Pittsburgh.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Battelino, Tadej
    University Medical Center–University Children's Hospital, Faculty of Medicine, Ljubljana, Slovenia .
    Castaño, Luis
    Hospital de Cruces–University of Basque Country, Barakaldo, Bizkaia, Spain .
    Greening, James
    Department of Paediatrics, Leicester Royal Infirmary, Leicester, UK.
    Kordonouri, Olga
    Diabetes Center for Children and Adolescents, Kinderkrankenhaus auf der Bult, Hannover, Germany .
    Otonkoski, Timo
    Children's Hospital, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland.
    Pozzilli, Paolo
    University Campus Bio-Medico, Rome, Italy.
    Robert, Jean-Jacques
    Hôpital Necker–Enfants Malades, Université René Descartes Paris 5, Paris, France.
    Veeze, Henk J.
    Stichting Diabeter, Rotterdam, the Netherlands .
    Palmer, Jerry
    Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, USA.
    Samuelsson, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Elding Larsson, Helena
    Lunds universitet, Sweden.
    Åman, Jan
    Örebro universitet, Sweden.
    Kärdell, Gunilla
    Neiderud, Jan
    Helsingborgs lasarett, Sweden.
    Lundström, Göran
    Länssjukhuset Kalmar, Sweden.
    Albinsson, Eva
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Carlsson, Annelie
    Skånes universitetssjukhus, Lund, Sweden.
    Nordvall, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Norrköping.
    Fors, Hans
    Sahlgrenska akademin vid Göteborgs universitet, Sweden.
    Arvidsson, Carl-Göran
    Centrallasarettet, Västerås, Sweden.
    Edvardson, Stig
    Centrallasarettet, Växjö, Sweden.
    Hanås, Ragnar
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Larsson, Karin
    Rathsman, Björn
    Sachsska Barnsjukhuset, Stockholm, Sweden.
    Forsgren, Henrik
    Desaix, Helena
    Forsander, Gun
    Göteborg University, Sweden.
    Nilsson, Nils-Östen
    Lasarettet i Halmstad, Sweden.
    Åkesson, Carl-Göran
    Keskinen, Päivi
    University of Tampere, Finland .
    Veijola, Riitta
    Uleåborgs universitetssjukhus, Finland.
    Talvitie, Timo
    Raile, Klemens
    Charite, Berlin, Germany.
    Kapellen, Thomas
    University of Leipzig, Germany.
    Burger, Walter
    Neu, Andreas
    University Children's Hospital, Tuebingen, Germany.
    Engelsberger, Ilse
    Heidtmann, Bettina
    Catholic Children’s Hospital Wilhelmstift, Hamburg, Germany.
    Bechtold, Suzanne
    Leslie, David
    Blizard Institute, Queen Mary University of London, UK.
    Chiarelli, Francesco
    University of Chieti, Italy.
    Cicognani, Alesandro
    University of Bologna, Italy.
    Chiumello, Giuseppe
    Vita-Salute University, Milan, Italy.
    Cerutti, Franco
    University of Turin, Italy.
    Zuccotti, Gian Vincenzo
    University of Milan, Italy.
    Gomez Gila, Ana
    Rica, Itxaso
    Barrio, Raquel
    Clemente, Maria
    López Garcia, Maria José
    Rodriguez, Mercedes
    Gonzalez, Isabel
    Lopez, Juan Pedro
    Oyarzabal, Mirentxu
    Reeser, H M
    Nuboer, Roos
    Stouthart, Pauline
    Bratina, Natasa
    Bratanic, Nina
    de Kerdanet, Marc
    Weill, Jacques
    Ser, Nicole
    Barat, Pascal
    Bertrand, Anne Marie
    Carel, Jean-Claude
    Reynaud, Rachel
    Coutant, Regis
    Baron, Sabine
    GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 366, no 5, p. 433-442Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.

    METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.

    RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.

    CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period.

  • 20.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Tavira Iglesias, Beatriz
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    More on Intralymphatic Injection of Autoantigen in Type 1 Diabetes REPLY2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 4, p. 403-405Article in journal (Other academic)
    Abstract [en]

    n/a

  • 21.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Wahlberg Topp, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Letter: Intralymphatic Injection of Autoantigen in Type 1 Diabetes in NEW ENGLAND JOURNAL OF MEDICINE, vol 376, issue 7, pp 697-6992017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 376, no 7, p. 697-699Article in journal (Other academic)
    Abstract [en]

    n/a

  • 22.
    Lyons, Paul A
    et al.
    Addenbrookes Hospital, England.
    Rayner, Tim F
    Addenbrookes Hospital, England.
    Trivedi, Sapna
    Addenbrookes Hospital, England.
    Holle, Julia U
    University Hospital Schleswig Holstein, Germany.
    Watts, Richard A
    Ipswich Hospital National Health Serv Trust, England University of E Anglia, England .
    Jayne, David R W
    Addenbrookes Hospital, England University of Cambridge, England .
    Baslund, Bo
    Copenhagen University Hospital, Denmark .
    Brenchley, Paul
    University of Manchester, England .
    Bruchfeld, Annette
    Karolinska University Hospital, Sweden .
    Chaudhry, Afzal N
    Addenbrookes Hospital, England University of Cambridge, England .
    Tervaert, Jan Willem Cohen
    Maastricht University, Netherlands .
    Deloukas, Panos
    Wellcome Trust Sanger Institute, England .
    Feighery, Conleth
    Trinity Coll Dublin, Ireland St James Hospital, Ireland .
    Gross, Wolfgang L
    University Hospital Schleswig Holstein, Germany Klinikum Bad Bramstedt, Germany .
    Guillevin, Loic
    University of Paris, France .
    Gunnarsson, Iva
    Karolinska University Hospital, Sweden .
    Harper, Lorraine
    University of Birmingham, England .
    Hruskova, Zdenka
    Charles University of Prague, Czech Republic Gen University Hospital, Czech Republic .
    Little, Mark A
    UCL, England .
    Martorana, Davide
    University Hospital, Italy .
    Neumann, Thomas
    University Hospital, Germany .
    Ohlsson, Sophie
    Karolinska Institute, Sweden Lund University, Sweden .
    Padmanabhan, Sandosh
    University of Glasgow, Scotland .
    Pusey, Charles D
    University of London Imperial Coll Science Technology and Med, England .
    Salama, Alan D
    UCL, England University of London Imperial Coll Science Technology and Med, England .
    Sanders, Jan-Stephan F
    University of Groningen, Netherlands .
    Savage, Caroline O
    GlaxoSmithKline, England .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Stegeman, Coen A
    University of Birmingham, England University of Groningen, Netherlands .
    Tesar, Vladimir
    Charles University of Prague, Czech Republic Gen University Hospital, Czech Republic .
    Vaglio, Augusto
    University Hospital, Italy .
    Wieczorek, Stefan
    Ruhr University of Bochum, Germany .
    Wilde, Benjamin
    Maastricht University, Netherlands .
    Zwerina, Jochen
    University of Erlangen Nurnberg, Germany Medical University of Vienna, Austria Medical University of Vienna, Austria .
    Rees, Andrew J
    Medical University of Vienna, Austria .
    Clayton, David G
    Addenbrookes Hospital, England.
    Smith, Kenneth G C
    Addenbrookes Hospital, England.
    Genetically Distinct Subsets within ANCA-Associated Vasculitis2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 3, p. 214-223Article in journal (Refereed)
    Abstract [en]

    BACKGROUND less thanbrgreater than less thanbrgreater thanAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegeners granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. less thanbrgreater than less thanbrgreater thanMETHODS less thanbrgreater than less thanbrgreater thanA genomewide association study was performed in a discovery cohort of 1233 U. K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. less thanbrgreater than less thanbrgreater thanRESULTS less thanbrgreater than less thanbrgreater thanWe found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding alpha(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2x10(-89), P = 5.6x10(-12), and P = 2.6x10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1x10(-8)). less thanbrgreater than less thanbrgreater thanCONCLUSIONS less thanbrgreater than less thanbrgreater thanThis study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.)

  • 23.
    Michaelsson, Karl
    et al.
    Uppsala University, Sweden.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Postmenopausal Osteoporosis2016In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 374, no 21, p. 2095-2097Article in journal (Other academic)
    Abstract [en]

    n/a

  • 24.
    Mirza, M. R.
    et al.
    Nordic Soc Gynecol Oncol, Denmark; Copenhagen University Hospital, Denmark.
    Monk, B. J.
    University of Arizona, AZ USA; Creighton University of Phoenix, AZ USA; Arizona Oncology Associates, AZ USA.
    Herrstedt, J.
    University of Southern Denmark, Denmark.
    Oza, A. M.
    University of Toronto, Canada.
    Mahner, S.
    Arbeitsgemeinschaft Gynakol Onkol, Germany; University of Munich, Germany.
    Redondo, A.
    GEICO, Spain; Hospital University of La Paz, Spain.
    Fabbro, M.
    French Investigator Grp Ovarian and Breast Cancer GIN, France; Institute Cancer Montpellier, France.
    Ledermann, J. A.
    UCL, England; UCL, England.
    Lorusso, D.
    Ist Nazl Tumori, Italy.
    Vergote, I.
    Luxembourg Gynecol Oncology Grp, Belgium; University of Leuven, Belgium.
    Ben-Baruch, N. E.
    Kaplan Medical Centre, Israel.
    Marth, C.
    AGO Austria, Austria; Medical University of Innsbruck, Austria.
    Madry, R.
    Central and Eastern European Gynecol Oncology Grp, Poland; Uniwersytet Medical Poznaniu, Poland.
    Christensen, R. D.
    University of Southern Denmark, Denmark.
    Berek, J. S.
    Stanford Comprehens Cancer Institute, CA USA.
    Dorum, A.
    Oslo University Hospital, Norway.
    Tinker, A. V.
    British Columbia Cancer Agency, Canada.
    du Bois, A.
    Kliniken Essen Mitte, Germany.
    Gonzalez-Martin, A.
    GEICO, Spain; MD Anderson Cancer Centre Madrid, Spain.
    Follana, P.
    GINECO, France; Centre Antoine Lacassagne, France.
    Benigno, B.
    Northside Hospital, GA USA.
    Rosenberg, Per
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Gilbert, L.
    McGill University, Canada.
    Rimel, B. J.
    Cedars Sinai Medical Centre, CA USA.
    Buscema, J.
    Arizona Oncology Associates, AZ USA.
    Balser, J. P.
    Veristat, MA USA.
    Agarwal, S.
    Tesaro, MA USA.
    Matulonis, U. A.
    Dana Farber Cancer Institute, MA 02115 USA.
    Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer2016In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 375, no 22, p. 2154-2164Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. METHODS In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2: 1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival. RESULTS Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P amp;lt; 0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications. CONCLUSIONS Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274.)

  • 25.
    Montalescot, Gilles
    et al.
    University of Paris 06, France.
    van t Hof, Arnoud W.
    Isala Clin, Netherlands.
    Lapostolle, Frederic
    Hop Avicenne, France.
    Silvain, Johanne
    University of Paris 06, France.
    Flensted Lassen, Jens
    Aarhus University Hospital, Denmark.
    Bolognese, Leonardo
    Azienda Osped Arezzo, Italy.
    Cantor, Warren J.
    University of Toronto, Canada.
    Cequier, Angel
    University of Barcelona, Spain.
    Chettibi, Mohamed
    Centre Hospital University of Franz Fanon, Algeria.
    Goodman, Shaun G.
    University of Toronto, Canada.
    Hammett, Christopher J.
    Royal Brisbane and Womens Hospital, Australia.
    Huber, Kurt
    Wilhelminenspital Stadt Wien, Austria.
    Janzon, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Merkely, Bela
    Semmelweis University, Hungary.
    Storey, Robert F.
    University of Sheffield, England.
    Zeymer, Uwe
    Klinikum Stadt Ludwigshafen, Germany; Institute Herzinfarktforsch Ludwigshafen, Germany.
    Stibbe, Olivier
    Brigade Sapeurs Pompiers Paris, France.
    Ecollan, Patrick
    CHU Pitie Salpetriere, France.
    Heutz, Wim M. J. M.
    Regionale Ambulance Voorziening, Netherlands.
    Swahn, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Collet, Jean-Philippe
    University of Paris 06, France.
    Willems, Frank F.
    Rijnstate Ziekenhuis, Netherlands.
    Baradat, Caroline
    AstraZeneca, France.
    Licour, Muriel
    AstraZeneca, France.
    Tsatsaris, Anne
    AstraZeneca, France.
    Vicaut, Eric
    Hop Lariboisiere, France.
    Hamm, Christian W.
    Kerckhoff Heart Centre, Germany.
    Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 11, p. 1016-1027Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The direct-acting platelet P2Y(12) receptor antagonist ticagrelor can reduce the incidence of major adverse cardiovascular events when administered at hospital admission to patients with ST-segment elevation myocardial infarction (STEMI). Whether prehospital administration of ticagrelor can improve coronary reperfusion and the clinical outcome is unknown. METHODS We conducted an international, multicenter, randomized, double-blind study involving 1862 patients with ongoing STEMI of less than 6 hours duration, comparing prehospital (in the ambulance) versus in-hospital (in the catheterization laboratory) treatment with ticagrelor. The coprimary end points were the proportion of patients who did not have a 70% or greater resolution of ST-segment elevation before percutaneous coronary intervention (PCI) and the proportion of patients who did not have Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography. Secondary end points included the rates of major adverse cardiovascular events and definite stent thrombosis at 30 days. RESULTS The median time from randomization to angiography was 48 minutes, and the median time difference between the two treatment strategies was 31 minutes. The two coprimary end points did not differ significantly between the prehospital and in-hospital groups. The absence of ST-segment elevation resolution of 70% or greater after PCI (a secondary end point) was reported for 42.5% and 47.5% of the patients, respectively. The rates of major adverse cardiovascular events did not differ significantly between the two study groups. The rates of definite stent thrombosis were lower in the prehospital group than in the in-hospital group (0% vs. 0.8% in the first 24 hours; 0.2% vs. 1.2% at 30 days). Rates of major bleeding events were low and virtually identical in the two groups, regardless of the bleeding definition used. CONCLUSIONS Prehospital administration of ticagrelor in patients with acute STEMI appeared to be safe but did not improve pre-PCI coronary reperfusion.

  • 26.
    OConnor, C.M.
    et al.
    Duke University.
    Starling, R.C.
    Cleveland Clinic.
    Hernandez, A.F.
    Duke University.
    Armstrong, P.W.
    University of Alberta.
    Dickstein, K.
    University of Bergen.
    Hasselblad, V.
    Duke University.
    Heizer, G.M.
    Duke University.
    Komajda, M.
    University Paris 06.
    Massie, B.M.
    University of California San Francisco.
    McMurray, J.J. V.
    University of Glasgow.
    Nieminen, M.S.
    Meilahti Hospital.
    Reist, C.J.
    Duke University.
    Rouleau, J.L.
    University of Montreal.
    Swedberg, K.
    University of Gothenburg.
    Adams, K.F.
    University of North Carolina,.
    Anker, S.D.
    IRCCS.
    Atar, D.
    Aker University Hospital.
    Battler, A.
    Rabin Medical Centre.
    Botero, R.
    Clin Medellin.
    Bohidar, N.R.
    Johnson and Johnson Pharmaceutical Research and Development.
    Butler, J.
    Emory University.
    Clausell, N.
    Hospital Clinic Porto Alegre.
    Corbalan, R.
    Pontificia University Catolica Chile.
    Costanzo, M.R.
    Edward Heart Hospital.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Deckelbaum, L.I.
    Johnson and Johnson Pharmaceutical Research and Development.
    Diaz, R.
    Estudios Cardiol Latino America.
    Dunlap, M.E.
    MetroHealth Medical Centre.
    Ezekowitz, J.A.
    University of Alberta.
    Feldman, D.
    Minneapolis Heart Institute.
    Felker, G.M.
    Duke University.
    Fonarow, G.C.
    Ronald Reagan UCLA Medical Centre.
    Gennevois, D.
    Janssen Alzheimer Immunotherapy.
    Gottlieb, S.S.
    University of Maryland Hospital.
    Hill, J.A.
    University of Florida.
    Hollander, J.E.
    University Penn.
    Howlett, J.G.
    Dalhousie University.
    Hudson, M.P.
    Edith and Benson Ford Heart and Vasc Institute.
    Kociol, R.D.
    Duke University.
    Krum, H.
    Monash University.
    Laucevicius, A.
    Lithuania.
    Levy, W.C.
    University Washington.
    Mendez, G.F.
    Alta Especialidad Hospital Especialidades,.
    Metra, M.
    University Brescia.
    Mittal, S.
    Escorts Heart Institute and Research Centre.
    Oh, B.-H.
    Seoul Natl University.
    Pereira, N.L.
    Mayo Clin.
    Ponikowski, P.
    Med University, Wroclaw.
    Wilson, W.H.
    Cleveland Clin.
    Tanomsup, S.
    Mahidol University.
    Teerlink, J.R.
    University Calif San Francisco.
    Triposkiadis, F.
    University Hospital Larissa.
    Troughton, R.W.
    University Otago.
    Voors, A.A.
    University Med Centre Groningen.
    Whellan, D.J.
    Thomas Jefferson University.
    Zannad, F.
    Centre Hospital University, Nancy, France.
    Califf, R.M.
    Duke University.
    Effect of Nesiritide in Patients with Acute Decompensated Heart Failure2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 365, no 1, p. 32-43Article in journal (Refereed)
    Abstract [en]

    Background Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. Methods We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. Results Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P = 0.03) and 24 hours (68.2% vs. 66.1%, P = 0.007), but the prespecified level for significance (P = 0.005 for both assessments or Pd less than= 0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P = 0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P = 0.11). Conclusions Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure.

  • 27.
    Schilcher, Jörg
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Koeppen, Veronika
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Michaelsson, Karl
    Uppsala University, Sweden.
    Risk of Atypical Femoral Fracture during and after Bisphosphonate Use2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 10, p. 974-976Article in journal (Other academic)
    Abstract [en]

    n/a

  • 28.
    Schilcher, Jörg
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Michaelsson, Karl
    Uppsala University.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Letter: Bisphosphonates and Atypical Femoral Shaft Fractures REPLY2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 365, no 4, p. 377-377Article in journal (Other academic)
    Abstract [en]

    n/a

  • 29.
    Schwartz, Gregory G
    et al.
    University of Colorado, CO USA Vet Affairs Medical Centre, CO USA .
    Olsson, Anders
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Abt, Markus
    F Hoffmann La Roche, Switzerland .
    Ballantyne, Christie M
    Baylor Coll Med, TX 77030 USA Methodist DeBakey Heart and Vasc Centre, TX 77030 USA .
    Barter, Philip J
    Heart Research Institute, Australia .
    Brumm, Jochen
    F Hoffmann La Roche, Switzerland .
    Chaitman, Bernard R
    St Louis University, MO 63103 USA .
    Holme, Ingar M
    Oslo University Hospital, Norway .
    Kallend, David
    F Hoffmann La Roche, Switzerland .
    Leiter, Lawrence A
    University of Toronto, Canada .
    Leitersdorf, Eran
    Hadassah Hebrew University, Israel .
    McMurray, John J V
    University of Glasgow, Scotland .
    Mundl, Hardi
    F Hoffmann La Roche, Switzerland .
    Nicholls, Stephen J
    University of Adelaide, Australia .
    Shah, Prediman K
    Cedars Sinai Heart Institute, CA USA .
    Tardif, Jean-Claude
    University of Montreal, Canada .
    Wright, R Scott
    Mayo Clin, MN USA .
    Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 22, p. 2089-2099Article in journal (Refereed)
    Abstract [en]

    BACKGROUND less thanbrgreater than less thanbrgreater thanIn observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. less thanbrgreater than less thanbrgreater thanMETHODS less thanbrgreater than less thanbrgreater thanWe randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. less thanbrgreater than less thanbrgreater thanRESULTS less thanbrgreater than less thanbrgreater thanAt the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P = 0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (Pandlt;0.001 for both comparisons). less thanbrgreater than less thanbrgreater thanCONCLUSIONS less thanbrgreater than less thanbrgreater thanIn patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.)

  • 30.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Genes that link nephritis to autoantibodies and innate immunity.2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 364, no 7, p. 679-680Article in journal (Other academic)
  • 31.
    Sitbon, Olivier
    et al.
    Universite Paris-Saclay, Le Kremlin-Bicetre, France.
    Channick, Richard
    Massachusetts General Hospital, Boston, USA.
    Chin, Kelly M
    Southwestern Medical Center, Dallas, USA.
    Frey, Aline
    Actelion Pharmaceuticals, Allschwil, Switzerland.
    Gaine, Sean
    National Pulmonary Hypertension Unit, Mater University Hospital, Dublin, Ireland.
    Galiè, Nazzareno
    University of Bologna, Bologna, Italy.
    Ghofrani, Hossein-Ardeschir
    University of Giessen andMarbury Lung Center, GermanCenter of Lund Research, Giessen, Germany.
    Hoeper, Marius M
    Hannover Medical School and German Center of Lung Research, Hannover, Germany.
    Lang, Irene M
    Division of Cardiology, Allgemeines Kramkenhasu, Vienna.
    Preiss, Ralph
    Actelion Pharmaceuticals, Allschwil, Switzerland.
    Rubin, Lewis J
    University of Calfornia, San Diego, USA.
    Di Scala, Lilla
    Actelion Pharmaceuticals, Allschwil, Switzerland.
    Tapson, Victor
    Sinai Medical Centre, Los Angeles, USA.
    Adzerikho, Igor
    MinskRegional Clinical Hospital, Minsk, Belarus.
    Liu, Jinming
    Shanghai Pulmonary Hospital, Shanghai, China.
    Moiseeva, Olga
    Federal Almazow North-West Medical Research Center, St Petersburg, Russia.
    Zeng, Xiaofeng
    Peking Union Medical College Hospital, Beijing, China.
    Simonneau, Gérald
    University Paris-Saclay, Le Kremlin-Bicetre, France.
    McLaughlin, Vallerie V
    University of Michigan Health System, Ann Arbor, USA.
    Selexipag for the Treatment of Pulmonary Arterial Hypertension2015In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 373, no 26Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension.

    METHODS: In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo).

    RESULTS: A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain.

    CONCLUSIONS: Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).

  • 32.
    Strålin, Kristoffer
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases.
    Eliasson, H
    Bäck, E
    An outbreak of primary pneumonic tularemia.2002In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 346, p. 1027-1029Article in journal (Refereed)
  • 33.
    Svedjeholm, Rolf
    et al.
    Östergötlands Läns Landsting.
    Dahlin, Lars-Göran
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting.
    Off-Pump versus On-Pump Coronary Bypass Surgery2004In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 350, no 17, p. 1791-1793Article in journal (Other academic)
    Abstract [en]

    [No abstract available]

  • 34.
    Thurin, A.
    et al.
    Department of Obstetrics, Inst. for Hlth. of Women/Children, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.
    Hausken, J.
    Fertility Unit, Haugesund Hospital, Haugesund, Norway.
    Hillensjo, T.
    Hillensjö, T., Fertility Center Scandinavia, Carlanderska Hospital, Göteborg, Sweden.
    Jablonowska, Barbara
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine.
    Pinborg, A.
    Fertility Clinic, Rigshospital, Copenhagen, Germany.
    Strandell, A.
    Department of Obstetrics, Inst. for Hlth. of Women/Children, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.
    Bergh, C.
    Department of Obstetrics, Inst. for Hlth. of Women/Children, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.
    Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization2004In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 351, no 23, p. 2392-2402Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The risks of premature birth and perinatal death are increased after in vitro fertilization. These risks are mainly due to the high incidence of multiple births, which relates to the number of embryos transferred. METHODS: We performed a randomized, multicenter trial to assess the equivalence of two approaches to in vitro fertilization with respect to the rates of pregnancy that result in at least one live birth and to compare associated rates of multiple gestation. Women less than 36 years of age who had at least two good-quality embryos were randomly assigned either to undergo transfer of a single fresh embryo and, if there was no live birth, subsequent transfer of a single frozen-and-thawed embryo, or to undergo a single transfer of two fresh embryos. Equivalence was defined as a difference of no more than 10 percentage points in the rates of pregnancy resulting in at least one live birth. RESULTS: Pregnancy resulting in at least one live birth occurred in 142 of 331 women (42.9 percent) in the double-embryo-transfer group as compared with 128 of 330 women (38.8 percent) in the single-embryo-transfer group (difference, 4.1 percentage points, 95 percent confidence interval, -3.4 to 11.6 percentage points), rates of multiple births were 33.1 percentand 0.8 percent, respectively (P<0.001). These results do not demonstrate equivalence of the two approaches in rates of live births, but they do indicate that any reduction in the rate of live births with the transfer of single embryos is unlikely to exceed 11.6 percentage points. CONCLUSIONS: In women under 36 years of age, transferring one fresh embryo and then, if needed, one frozen-and-thawed embryo dramatically reduces the rate of multiple births while achieving a rate of live births that is not substantially lower than the rate that is achievable with a double-embryo transfer. Copyright © 2004 Massachusetts Medical Society.

  • 35.
    Westermark, Gunilla
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Westermark, P.
    Uppsala University, SE-751-85 Uppsala, Sweden.
    Berne, C.
    Uppsala University, SE-751-85 Uppsala, Sweden.
    Korsgren, O.
    Uppsala University, SE-751-85 Uppsala, Sweden.
    Widespread amyloid deposition in transplanted human pancreatic islets2008In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 359, no 9, p. 977-979Other (Other academic)
    Abstract [en]

    [No abstract available]

  • 36. Wolfraim, Lawrence A
    et al.
    Fernandez, Tania M
    Mamura, Mizuko
    Fuller, Walter L
    Kumar, Rajesh
    Cole, Diane E
    Byfield, Stacey
    Felici, Angelina
    Flanders, Kathleen C
    Walz, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Roberts, Anita B
    Aplan, Peter D
    Balis, Frank M
    Letterio, John J
    Loss of Smad3 in acute T-cell lymphoblastic leukemia2004In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 351, no 6, p. 552-559Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The receptors for transforming growth factor β (TGF-β) and their signaling intermediates make up an important tumor-suppressor pathway. The role of one of these intermediates - Smad3 - in the pathogenesis of lymphoid neoplasia is unknown. METHODS: We measured Smad3 messenger RNA (mRNA) and protein in leukemia cells obtained at diagnosis from 19 children with acute leukemia, including 10 with T-cell acute lymphoblastic leukemia (ALL), 7 with pre-B-cell ALL, and 2 with acute nonlymphoblastic leukemia (ANLL). All nine exons of the SMAD3 gene (MADH3) were sequenced. Mice in which one or both alleles of Smad3 were inactivated were used to evaluate the role of Smad3 in the response of normal T cells to TGF-β and in the susceptibility to spontaneous leukemogenesis in mice in which both alleles of the tumor suppressor p27Kip1 were deleted. RESULTS: Smad3 protein was absent in T-cell ALL but present in pre-B-cell ALL and ANLL. No mutations were found in the MADH3 gene in T-cell ALL, and Smad3 mRNA was present in T-cell ALL and normal T cells at similar levels. In mice, the loss of one allele for Smad3 impairs the inhibitory effect of TGF-β on the proliferation of normal T cells and works in tandem with the homozygous inactivation of p27Kip1 to promote T-cell leukemogenesis. CONCLUSIONS: Loss of Smad3 protein is a specific feature of pediatric T-cell ALL. A reduction in Smad3 expression and the loss of p27Kip1 work synergistically to promote T-cell leukemogenesis in mice.

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