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  • 1.
    Bellani, Giacomo
    et al.
    Univ Milano Bicocca, Sch Med & Surg, Monza, Italy.;San Gerardo Hosp, Dept Emergency & Intens Care, Monza, Italy..
    Laffey, John G.
    St Michaels Hosp, Dept Anesthesia & Crit Care Med, Keenan Res Ctr Biomed Sci, Toronto, ON, Canada.;Univ Toronto, Dept Anesthesia, 30 Bond St, Toronto, ON M5B 1W8, Canada.;Univ Toronto, Dept Physiol, 30 Bond St, Toronto, ON M5B 1W8, Canada.;Univ Toronto, Interdept Div Crit Care Med, 30 Bond St, Toronto, ON M5B 1W8, Canada..
    Pham, Tai
    Grp Hosp Hop Univ Est Parisien, Hop Tenon, AP HP, Unite Reanimat Med Chirurgicale,Pole Thorax Voies, Paris, France.;Univ Paris Diderot, Sorbonne Paris Cite, ECSTRA Team, UMR 1153,Inserm, Paris, France.;Univ Paris Est Creteil, UMR 915, INSERM, Creteil, France..
    Fan, Eddy
    Univ Toronto, Interdept Div Crit Care Med, 30 Bond St, Toronto, ON M5B 1W8, Canada.;Univ Hlth Network, Dept Med, Toronto, ON, Canada.;Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada.;Univ Toronto, Inst Hlth Policy Management & Evaluat, 30 Bond St, Toronto, ON M5B 1W8, Canada..
    Brochard, Laurent
    Univ Toronto, Interdept Div Crit Care Med, 30 Bond St, Toronto, ON M5B 1W8, Canada.;St Michaels Hosp, Keenan Res Ctr, Li Ka Shing Knowledge Inst, 30 Bond St, Toronto, ON M5B 1W8, Canada..
    Esteban, Andres
    Univ Toronto, Interdept Div Crit Care Med, 30 Bond St, Toronto, ON M5B 1W8, Canada.;Hosp Univ Getafe, CIBER Enfermedades Respiratorias, Madrid, Spain..
    Gattinoni, Luciano
    Univ Milan, Ist Anestesia & Rianimaz, Osped Maggiore, Ist Ricovero & Cura Carattere Sci, Milan, Italy..
    van Haren, Frank
    Canberra Hosp, Intens Care Unit, Canberra, ACT, Australia.;Australian Natl Univ, Canberra, ACT, Australia..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    McAuley, Daniel F.
    Queens Univ Belfast, Ctr Med Expt, Belfast, Antrim, North Ireland.;Wellcome Wolfson Inst Expt Med, Belfast, Antrim, North Ireland.;Royal Victoria Hosp, Reg Intens Care Unit, Grosvenor Rd, Belfast BT12 6BA, Antrim, North Ireland..
    Ranieri, Marco
    Policlin Umberto 1, SAPIENZA Univ ROMA, Dipartimento Anestesia & Rianimaz, Viale Policlin 155, I-00161 Rome, Italy..
    Rubenfeld, Gordon
    Univ Toronto, Interdept Div Crit Care Med, 30 Bond St, Toronto, ON M5B 1W8, Canada.;Sunnybrook Hlth Sci Ctr, Program Trauma Emergency & Crit Care, Toronto, ON M4N 3M5, Canada..
    Thompson, B. Taylor
    Harvard Univ, Sch Med, Div Pulm, Boston, MA USA.;Harvard Univ, Massachusetts Gen Hosp, Sch Med, Crit Care Unit,Dept Med, Boston, MA USA..
    Wrigge, Hermann
    Univ Leipzig, Dept Anesthesiol & Intens Care Med, Liebigstr 20, D-04103 Leipzig, Germany..
    Slutsky, Arthur S.
    Univ Toronto, Interdept Div Crit Care Med, 30 Bond St, Toronto, ON M5B 1W8, Canada.;Univ Toronto, St Michaels Hosp, Keenan Res Ctr, Li Ka Shing Knowledge Inst, 30 Bond St, Toronto, ON M5B 1W8, Canada..
    Pesenti, Antonio
    Univ Milan, Ist Anestesia & Rianimaz, Osped Maggiore, Ist Ricovero & Cura Carattere Sci, Milan, Italy..
    Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries2016In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 315, no 8, p. 788-800Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Limited information exists about the epidemiology, recognition, management, and outcomes of patients with the acute respiratory distress syndrome (ARDS). OBJECTIVES To evaluate intensive care unit (ICU) incidence and outcome of ARDS and to assess clinician recognition, ventilation management, and use of adjuncts-for example prone positioning-in routine clinical practice for patients fulfilling the ARDS Berlin Definition. DESIGN, SETTING, AND PARTICIPANTS The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents. EXPOSURES Acute respiratory distress syndrome. MAIN OUTCOMES AND MEASURES The primary outcome was ICU incidence of ARDS. Secondary outcomes included assessment of clinician recognition of ARDS, the application of ventilatory management, the use of adjunctive interventions in routine clinical practice, and clinical outcomes from ARDS. RESULTS Of 29 144 patients admitted to participating ICUs, 3022 (10.4%) fulfilled ARDS criteria. Of these, 2377 patients developed ARDS in the first 48 hours and whose respiratory failure was managed with invasive mechanical ventilation. The period prevalence of mild ARDS was 30.0%(95% CI, 28.2%-31.9%); of moderate ARDS, 46.6%(95% CI, 44.5%-48.6%); and of severe ARDS, 23.4%(95% CI, 21.7%-25.2%). ARDS represented 0.42 cases per ICU bed over 4 weeks and represented 10.4%(95% CI, 10.0%-10.7%) of ICU admissions and 23.4% of patients requiring mechanical ventilation. Clinical recognition of ARDS ranged from 51.3% (95% CI, 47.5%-55.0%) in mild to 78.5%(95% CI, 74.8%-81.8%) in severe ARDS. Less than two-thirds of patients with ARDS received a tidal volume 8 of mL/kg or less of predicted body weight. Plateau pressure was measured in 40.1%(95% CI, 38.2-42.1), whereas 82.6%(95% CI, 81.0%-84.1%) received a positive end-expository pressure (PEEP) of less than 12 cm H2O. Prone positioning was used in 16.3%(95% CI, 13.7%-19.2%) of patients with severe ARDS. Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning. Hospital mortality was 34.9%(95% CI, 31.4%-38.5%) for those with mild, 40.3%(95% CI, 37.4%-43.3%) for those with moderate, and 46.1%(95% CI, 41.9%-50.4%) for those with severe ARDS. CONCLUSIONS AND RELEVANCE Among ICUs in 50 countries, the period prevalence of ARDS was 10.4% of ICU admissions. This syndrome appeared to be underrecognized and undertreated and associated with a high mortality rate. These findings indicate the potential for improvement in the management of patients with ARDS.

  • 2. Blennow, Mats
    et al.
    Ewald, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Fellman, Vineta
    Hellström-Westas, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Källén, Karin
    Lagercrantz, Hugo
    Marsál, Karel
    Dept of Obstetrics and Gynecology, Lund University, Lund, Sweden.
    Norden-Lindeberg, Solveig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Norman, Mikael
    Serenius, Fredrik
    Westgren, Magnus
    Wennergren, Margareta
    Holmström, Gerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Strömberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    One-year survival of extremely preterm infants after active perinatal care in Sweden: The EXPRESS Group Members2009In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 301, no 21, p. 2225-2233Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Up-to-date information on infant survival after extremely preterm birth is needed for assessing perinatal care services, clinical guidelines, and parental counseling. OBJECTIVE: To determine the 1-year survival in all infants born before 27 gestational weeks in Sweden during 2004-2007. DESIGN, SETTING, AND PATIENTS: Population-based prospective observational study of extremely preterm infants (707 live-born and 304 stillbirths) born to 887 mothers in 904 deliveries (102 multiple births) in all obstetric and neonatal units in Sweden from April 1, 2004, to March 31, 2007. MAIN OUTCOME MEASURES: Infant survival to 365 days and survival without major neonatal morbidity (intraventricular hemorrhage grade >2, retinopathy of prematurity stage >2, periventricular leukomalacia, necrotizing enterocolitis, severe bronchopulmonary dysplasia). Associations between perinatal interventions and survival. RESULTS: The incidence of extreme prematurity was 3.3 per 1000 infants. Overall perinatal mortality was 45% (from 93% at 22 weeks to 24% at 26 weeks), with 30% stillbirths, including 6.5% intrapartum deaths. Of live-born infants, 91% were admitted to neonatal intensive care and 70% survived to 1 year of age (95% confidence interval [CI], 67%-73%). The Kaplan-Meier survival estimates for 22, 23, 24, 25, and 26 weeks were 9.8% (95% CI, 4%-23%), 53% (95% CI, 44%-63%), 67% (95% CI, 59%-75%), 82% (95% CI, 76%-87%), and 85% (95% CI, 81%-90%), respectively. Lower risk of infant death was associated with tocolytic treatment (adjusted for gestational age odds ratio [OR], 0.43; 95% CI, 0.36-0.52), antenatal corticosteroids (OR, 0.44; 95% CI, 0.24-0.81), surfactant treatment within 2 hours after birth (OR, 0.47; 95% CI, 0.32-0.71), and birth at a level III hospital (OR, 0.49; 95% CI, 0.32-0.75). Among 1-year survivors, 45% had no major neonatal morbidity. CONCLUSION: During 2004 to 2007, 1-year survival of infants born alive at 22 to 26 weeks of gestation in Sweden was 70% and ranged from 9.8% at 22 weeks to 85% at 26 weeks.

  • 3. Borges, João Batista
    et al.
    Carvalho, Carlos Roberto Ribeiro
    Amato, Marcelo Britto Passos
    Ventilation strategies for acute lung injury and acute respiratory distress syndrome2008In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 300, no 1, p. 41-reply: 42Article in journal (Refereed)
  • 4.
    Burt, Richard K.
    et al.
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Balabanov, Roumen
    Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sharrack, Basil
    Sheffield Teaching Hosp NHS Fdn Trust, Dept Neurosci, Sheffield, S Yorkshire, England;Sheffield Teaching Hosp NHS Fdn Trust, Sheffield NIHR Translat Neurosci BBC, Sheffield, S Yorkshire, England;Univ Sheffield, Sheffield, S Yorkshire, England.
    Snowden, John A.
    Univ Sheffield, Sheffield, S Yorkshire, England;Sheffield Teaching Hosp NHS Fdn Trust, Dept Haematol & Oncol, Sheffield, S Yorkshire, England;Sheffield Teaching Hosp NHS Fdn Trust, Dept Metab, Sheffield, S Yorkshire, England.
    Oliveira, Maria Carolina
    Univ Sao Paulo, Ctr Cell Based Therapy, Dept Internal Med, Ribeirao Preto Med Sch, Ribeirao Preto, Brazil.
    Fagius, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Rose, John
    Univ Utah, Dept Neurol, Salt Lake City, UT USA.
    Nelson, Flavia
    Univ Minnesota, Dept Neurol, Div Multiple Sclerosis, Minneapolis, MN 55455 USA.
    Barreira, Amilton Antunes
    Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Neurosci & Behav Sci, Ribeirao Preto, Brazil.
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Han, Xiaoqiang
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Moraes, Daniela
    Univ Sao Paulo, Ctr Cell Based Therapy, Dept Internal Med, Ribeirao Preto Med Sch, Ribeirao Preto, Brazil.
    Morgan, Amy
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Quigley, Kathleen
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Yaung, Kimberly
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Buckley, Regan
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Alldredge, Carri
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Clendenan, Allison
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Calvario, Michelle A.
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Henry, Jacquelyn
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Jovanovic, Borko
    Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA.
    Helenowski, Irene B.
    Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA.
    Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial2019In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 321, no 2, p. 165-174Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS).

    OBJECTIVE To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression.

    DESIGN, SETTING, AND PARTICIPANTS Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018.

    INTERVENTIONS Patients were randomized to receive HSCT along with cyclophosphamide (200mg/kg) and antithymocyte globulin (6mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55).

    MAIN OUTCOMES AND MEASURES The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. RESULTS Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference,-1.7; 95% CI,-2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events).

    CONCLUSIONS AND RELEVANCE In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety.

  • 5. Burt, Richard K
    et al.
    Balabanov, Roumen
    Han, Xiaoqiang
    Sharrack, Basil
    Morgan, Amy
    Quigley, Kathleeen
    Yaung, Kim
    Helenowski, Irene B
    Jovanovic, Borko
    Spahovic, Dzemila
    Arnautovic, Indira
    Lee, Daniel C
    Benefield, Brandon C
    Futterer, Stephen
    Oliveira, Maria Carolina
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis2015In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 313, no 3, p. 275-284Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability.

    OBJECTIVE: To determine the association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS.

    DESIGN, SETTING, AND PARTICIPANTS: Case series of patients with relapsing-remitting MS (n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014.

    INTERVENTIONS: Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells.

    MAIN OUTCOMES AND MEASURES: Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan.

    RESULTS: Outcome analysis was available for 145 patients with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, -0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128).

    CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.

  • 6. Carrero, Juan Jesus
    et al.
    Evans, Marie
    Szummer, Karolina
    Spaak, Jonas
    Lindhagen, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Edfors, Robert
    Stenvinkel, Peter
    Jacobson, Stefan H.
    Jernberg, Tomas
    Warfarin, Kidney Dysfunction, and Outcomes Following Acute Myocardial Infarction in Patients With Atrial Fibrillation2014In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 311, no 9, p. 919-928Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Conflicting evidence exists regarding the association between warfarin treatment, death, and ischemic stroke incidence in patients with advanced chronic kidney disease (CKD) and atrial fibrillation. OBJECTIVE To study outcomes associated with warfarin treatment in relation to kidney function among patients with established cardiovascular disease and atrial fibrillation. DESIGN, SETTING, AND PARTICIPANTS Observational, prospective, multicenter cohort study from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry (2003-2010), which includes all Swedish hospitals that provide care for acute cardiac diseases. Participants included consecutive survivors of an acute myocardial infarction (MI) with atrial fibrillation and known serum creatinine (N = 24 317), including 21.8% who were prescribed warfarin at discharge. Chronic kidney disease stages were classified according to estimated glomerular filtration rate (eGFR). MAIN OUTCOMES AND MEASURES (1) Composite end point analysis of death, readmission due to MI, or ischemic stroke; (2) bleeding (composite of readmission due to hemorrhagic stroke, gastrointestinal bleeding, bleeding causing anemia, and others); or (3) the aggregate of these 2 outcomes within 1 year from discharge date. RESULTS A total of 5292 patients (21.8%) were treated with warfarin at discharge, and 51.7% had manifest CKD (eGFR <60 mL/min/1.73 m(2) [eGFR(<60)]). Compared with no warfarin use, warfarin was associated with a lower risk of the first composite outcome (n = 9002 events) in each CKD stratum for event rates per 100 person-years: eGFR(>60) event rate, 28.0 for warfarin vs 36.1 for no warfarin; adjusted hazard ratio (HR), 0.73 (95% CI, 0.65 to 0.81); eGFR(>30-60): event rate, 48.5 for warfarin vs 63.8 for no warfarin; HR, 0.73 (95% CI, 0.66 to 0.80); eGFR(>15-30): event rate, 84.3 for warfarin vs 110.1 for no warfarin; HR, 0.84 (95% CI, 0.70-1.02); eGFR(<= 15): event rate, 83.2 for warfarin vs 128.3 for no warfarin; HR, 0.57 (95% CI, 0.37-0.86). The risk of bleeding (n = 1202 events) was not significantly higher in patients treated with warfarin in any CKD stratum for event rates per 100 person-years: eGFR(>60) event rate, 5.0 for warfarin vs 4.8 for no warfarin; HR, 1.10 (95% CI, 0.86-1.41); eGFR(>30-60) event rate, 6.8 forwarfarin vs 6.3 for no warfarin; HR, 1.04 (95% CI, 0.81-1.33); eGFR(>15-30) event rate, 9.3 forwarfarin vs 10.4 for nowarfarin; HR, 0.82 (95% CI, 0.48-1.39); eGFR(<= 15) event rate, 9.1 forwarfarin vs 13.5 for nowarfarin; HR, 0.52 (95% CI, 0.16-1.65). Warfarin use in each CKD stratum was associated with lower hazards of the aggregate outcome (n = 9592 events) for event rates per 100 person-years: eGFR(>60) event rate, 32.1 for warfarin vs 40.0 for no warfarin; HR, 0.76 (95% CI, 0.69-0.84); eGFR(>30-60) event rate, 53.6 forwarfarin vs 69.0 for nowarfarin; HR, 0.75 (95% CI, 0.68-0.82); eGFR(>15-30) event rate, 90.2 forwarfarin vs 117.7 for nowarfarin; HR, 0.82 (95% CI, 0.68-0.99); eGFR(<= 15) event rate, 86.2 forwarfarin vs 138.2 for nowarfarin; HR, 0.55 (95% CI, 0.37-0.83). CONCLUSIONS AND RELEVANCE Warfarin treatment was associated with a lower 1-year risk for the composite outcome of death, MI, and ischemic stroke without a higher risk of bleeding in consecutive acute MI patients with atrial fibrillation. This association was not related to the severity of concurrent CKD.

  • 7.
    Chang, Zheng
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England..
    Lichtenstein, Paul
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Långström, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Larsson, Henrik
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Univ Orebro, Sch Med Sci, Orebro, Sweden..
    Fazel, Seena
    Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England..
    Association Between Prescription of Major Psychotropic Medications and Violent Reoffending After Prison Release2016In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 316, no 17, p. 1798-1807Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Individuals released from prison have high rates of violent reoffending, and there is uncertainty about whether pharmacological treatments reduce reoffending risk. OBJECTIVE To investigate the associations between major classes of psychotropic medications and violent reoffending. DESIGN, SETTING, AND PARTICIPANTS This cohort study included all released prisoners in Sweden from July 1, 2005, to December 31, 2010, through linkage of population-based registers. Rates of violent reoffending during medicated periods were compared with rates during nonmedicated periods using within-individual analyses. Follow-up ended December 31, 2013. EXPOSURES Periods with or without dispensed prescription of psychotropic medications (antipsychotics, antidepressants, psychostimulants, drugs used in addictive disorders, and antiepileptic drugs) after prison release. Prison-based psychological treatments were investigated as a secondary exposure. MAIN OUTCOMES AND MEASURES Violent crime after release from prison. RESULTS The cohort included 22 275 released prisoners (mean [SD] age, 38 [13] years; 91.9% male). During follow-up (median, 4.6 years; interquartile range, 3.0-6.4 years), 4031 individuals (18.1%) had 5653 violent reoffenses. The within-individual hazard ratio (HR) associated with dispensed antipsychotics was 0.58 (95% CI, 0.39-0.88), based on 100 events in 1596 person-years during medicated periods and 1044 events in 11 026 person-years during nonmedicated periods, equating to a risk difference of 39.7 (95% CI, 11.3-57.7) fewer violent reoffenses per 1000 person-years. The within-individual HR associated with dispensed psychostimulants was 0.62 (95% CI, 0.40-0.98), based on 94 events in 1648 person-years during medicated periods and 513 events in 4553 person-years during nonmedicated periods, equating to a risk difference of 42.8 (95% CI, 2.2-67.6) fewer violent reoffenses per 1000 person-years. The within-individual HR associated with dispensed drugs for addictive disorders was 0.48 (95% CI, 0.23-0.97), based on 46 events in 1168 person-years during medicated periods and 1103 events in 15 725 person-years during nonmedicated periods, equating to a risk difference of 36.4 (95% CI, 2.1-54.0) fewer violent reoffenses per 1000 person-years. In contrast, antidepressants and antiepileptics were not significantly associated with violent reoffending rates (HR = 1.09 [95% CI, 0.83-1.43] and 1.14 [95% CI, 0.79-1.65], respectively). The most common prison-based program was psychological treatments for substance abuse, associated with an HR of 0.75 (95% CI, 0.63-0.89), which equated to a risk difference of 23.2 (95% CI, 10.3-34.1) fewer violent reoffenses per 1000 person-years. CONCLUSIONS AND RELEVANCE Among released prisoners in Sweden, rates of violent reoffending were lower during periods when individiduals were dispensed antipsychotics, psychostimulants, and drugs for addictive disorders, compared with periods in which they were not dispensed these medications. Further research is needed to understand the causal nature of this association.

  • 8. Cnattingius, Sven
    et al.
    Villamor, Eduardo
    Johansson, Stefan
    Bonamy, Anna-Karin Edstedt
    Persson, Martina
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Granath, Fredrik
    Maternal Obesity and Risk of Preterm Delivery2013In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 309, no 22, p. 2362-2370Article in journal (Refereed)
    Abstract [en]

    Importance Preterm birth is a leading cause of infant mortality, morbidity, and long-term disability, and these risks increase with decreasing gestational age. Obesity increases the risk of preterm delivery, but the associations between overweight and obesity and subtypes of preterm delivery are not clear. Objective To study the associations between early pregnancy body mass index (BMI) and risk of preterm delivery by gestational age and by precursors of preterm delivery. Design, Setting, and Participants Population-based cohort study of women with live singleton births in Sweden from 1992 through 2010. Maternal and pregnancy characteristics were obtained from the nationwide Swedish Medical Birth Register. Main Outcomes and Measures Risks of preterm deliveries (extremely, 22-27 weeks; very, 28-31 weeks; and moderately, 32-36 weeks). These outcomes were further characterized as spontaneous (related to preterm contractions or preterm premature rupture of membranes) and medically indicated preterm delivery (cesarean delivery before onset of labor or induced onset of labor). Risk estimates were adjusted for maternal age, parity, smoking, education, height, mother's country of birth, and year of delivery. Results Among 1 599 551 deliveries with information on early pregnancy BMI, 3082 were extremely preterm, 6893 were very preterm, and 67 059 were moderately preterm. Risks of extremely, very, and moderately preterm deliveries increased with BMI and the overweight and obesity-related risks were highest for extremely preterm delivery. Among normal-weight women (BMI 18.5-<25), the rate of extremely preterm delivery was 0.17%. As compared with normal-weight women, rates (%) and adjusted odds ratios (ORs [95% CIs]) of extremely preterm delivery were as follows: BMI 25 to less than 30 (0.21%; OR, 1.26; 95% CI, 1.15-1.37), BMI 30 to less than 35 (0.27%; OR, 1.58; 95% CI, 1.39-1.79), BMI 35 to less than 40 (0.35%; OR, 2.01; 95% CI, 1.66-2.45), and BMI of 40 or greater (0.52%; OR, 2.99; 95% CI, 2.28-3.92). Risk of spontaneous extremely preterm delivery increased with BMI among obese women (BMI >= 30). Risks of medically indicated preterm deliveries increased with BMI among overweight and obese women. Conclusions and Relevance In Sweden, maternal overweight and obesity during pregnancy were associated with increased risks of preterm delivery, especially extremely preterm delivery. These associations should be assessed in other populations.

  • 9. Coresh, Josef
    et al.
    Turin, Tanvir Chowdhury
    Matsushita, Kunihiro
    Sang, Yingying
    Ballew, Shoshana H
    Appel, Lawrence J
    Arima, Hisatomi
    Chadban, Steven J
    Cirillo, Massimo
    Djurdjev, Ognjenka
    Green, Jamie A
    Heine, Gunnar H
    Inker, Lesley A
    Irie, Fujiko
    Ishani, Areef
    Ix, Joachim H
    Kovesdy, Csaba P
    Marks, Angharad
    Ohkubo, Takayoshi
    Shalev, Varda
    Shankar, Anoop
    Wen, Chi Pang
    de Jong, Paul E
    Iseki, Kunitoshi
    Stengel, Benedicte
    Gansevoort, Ron T
    Levey, Andrew S
    Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality2014In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 311, no 24, p. 2518-2531Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of −57% or greater) is a late event.

    OBJECTIVE: To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated.

    DATA SOURCES AND STUDY SELECTION: Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data.

    DATA EXTRACTION AND SYNTHESIS: Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012.

    MAIN OUTCOMES AND MEASURES: End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR.

    RESULTS: The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of −57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of −30%. However, changes of −30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of −57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99% (95% CI, 95%-100%) for estimated GFR change of −57%, was 83% (95% CI, 71%-93%) for estimated GFR change of −40%, and was 64% (95% CI, 52%-77%) for estimated GFR change of −30% vs 18% (95% CI, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% CI, 71%-82%), 60% (95% CI, 56%-63%), and 50% (95% CI, 47%-52%) vs 32% (95% CI, 31%-33%), showing a similar but weaker pattern.

    CONCLUSIONS AND RELEVANCE: Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.

  • 10. Di Angelantonio, Emanuele
    et al.
    Gao, Pei
    Khan, Hassan
    Butterworth, Adam S.
    Wormser, David
    Kaptoge, Stephen
    Seshasai, Sreenivasa Rao Kondapally
    Thompson, Alex
    Sarwar, Nadeem
    Willeit, Peter
    Ridker, Paul M.
    Barr, Elizabeth L. M.
    Khaw, Kay-Tee
    Psaty, Bruce M.
    Brenner, Hermann
    Balkau, Beverley
    Dekker, Jacqueline M.
    Lawlor, Debbie A.
    Daimon, Makoto
    Willeit, Johann
    Njolstad, Inger
    Nissinen, Aulikki
    Brunner, Eric J.
    Kuller, Lewis H.
    Price, Jackie F.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Knuiman, Matthew W.
    Feskens, Edith J. M.
    Verschuren, W. M. M.
    Wald, Nicholas
    Bakker, Stephan J. L.
    Whincup, Peter H.
    Ford, Ian
    Goldbourt, Uri
    Gomez-de-la-Camara, Agustin
    Gallacher, John
    Simons, Leon A.
    Rosengren, Annika
    Sutherland, Susan E.
    Bjorkelund, Cecilia
    Blazer, Dan G.
    Wassertheil-Smoller, Sylvia
    Onat, Altan
    Ibanez, Alejandro Marin
    Casiglia, Edoardo
    Jukema, J. Wouter
    Simpson, Lara M.
    Giampaoli, Simona
    Nordestgaard, Borge G.
    Selmer, Randi
    Wennberg, Patrik
    Kauhanen, Jussi
    Salonen, Jukka T.
    Dankner, Rachel
    Barrett-Connor, Elizabeth
    Kavousi, Maryam
    Gudnason, Vilmundur
    Evans, Denis
    Wallace, Robert B.
    Cushman, Mary
    D'Agostino, Ralph B., Sr.
    Umans, Jason G.
    Kiyohara, Yutaka
    Nakagawa, Hidaeki
    Sato, Shinichi
    Gillum, Richard F.
    Folsom, Aaron R.
    van der Schouw, Yvonne T.
    Moons, Karel G.
    Griffin, Simon J.
    Sattar, Naveed
    Wareham, Nicholas J.
    Selvin, Elizabeth
    Thompson, Simon G.
    Danesh, John
    Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease2014In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 311, no 12, p. 1225-1233Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE The value of measuring levels of glycated hemoglobin (HbA(1c)) for the prediction of first cardiovascular events is uncertain. OBJECTIVE To determine whether adding information on HbA(1c) values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS Analysis of individual-participant data available from 73 prospective studies involving 294 998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (>= 7.5%) risk. RESULTS During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20 840 incident fatal and nonfatal CVD outcomes (13 237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA(1c) values and CVD risk. The association between HbA(1c) values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA(1c) was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA(1c) assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels. CONCLUSIONS AND RELEVANCE In a study of individuals without known CVD or diabetes, additional assessment of HbA(1c) values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.

  • 11. Di Angelantonio, Emanuele
    et al.
    Gao, Pei
    Pennells, Lisa
    Kaptoge, Stephen
    Caslake, Muriel
    Thompson, Alexander
    Butterworth, Adam S.
    Sarwar, Nadeem
    Wormser, David
    Saleheen, Danish
    Ballantyne, Christie M.
    Psaty, Bruce M.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ridker, Paul M.
    Nagel, Dorothea
    Gillum, Richard F.
    Ford, Ian
    Ducimetiere, Pierre
    Kiechl, Stefan
    Dullaart, Robin P. F.
    Assmann, Gerd
    D'Agostino, Ralph B.
    Dagenais, Gilles R.
    Cooper, Jackie A.
    Kromhout, Daan
    Onat, Altan
    Tipping, Robert W.
    Gomez-de-la-Camara, Agustin
    Rosengren, Annika
    Sutherland, Susan E.
    Gallacher, John
    Fowkes, F. Gerry R.
    Casiglia, Edoardo
    Hofman, Albert
    Salomaa, Veikko
    Barrett-Connor, Elizabeth
    Clarke, Robert
    Brunner, Eric
    Jukema, J. Wouter
    Simons, Leon A.
    Sandhu, Manjinder
    Wareham, Nicholas J.
    Khaw, Kay-Tee
    Kauhanen, Jussi
    Salonen, Jukka T.
    Howard, William J.
    Nordestgaard, Borge G.
    Wood, Angela M.
    Thompson, Simon G.
    Boekholdt, S. Matthijs
    Sattar, Naveed
    Packard, Chris
    Gudnason, Vilmundur
    Danesh, John
    Lipid-Related Markers and Cardiovascular Disease Prediction2012In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 307, no 23, p. 2499-2506Article in journal (Refereed)
    Abstract [en]

    Context

    The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated.

    Objective 

    To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction.

    Design, Setting, and Participants 

    Individual records were available for 165 544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15 126 incident fatal or nonfatal CVD outcomes (10 132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years).

    Main Outcome Measures 

    Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk.

    Results 

    The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100 000 adults aged 40 years or older, 15 436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.

    Conclusion 

    In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

  • 12. Di Angelantonio, Emanuele
    et al.
    Kaptoge, Stephen
    Wormser, David
    Willeit, Peter
    Butterworth, Adam S.
    Bansal, Narinder
    O'Keeffe, Linda M.
    Gao, Pei
    Wood, Angela M.
    Burgess, Stephen
    Freitag, Daniel F.
    Pennells, Lisa
    Peters, Sanne A.
    Hart, Carole L.
    Haheim, Lise Lund
    Gillum, Richard F.
    Nordestgaard, Borge G.
    Psaty, Bruce M.
    Yeap, Bu B.
    Knuiman, Matthew W.
    Nietert, Paul J.
    Kauhanen, Jussi
    Salonen, Jukka T.
    Kuller, Lewis H.
    Simons, Leon A.
    van der Schouw, Yvonne T.
    Barrett-Connor, Elizabeth
    Selmer, Randi
    Crespo, Carlos J.
    Rodriguez, Beatriz
    Verschuren, W. M. Monique
    Salomaa, Veikko
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    van der Harst, Pim
    Bjorkelund, Cecilia
    Wilhelmsen, Lars
    Wallace, Robert B.
    Brenner, Hermann
    Amouyel, Philippe
    Barr, Elizabeth L. M.
    Iso, Hiroyasu
    Onat, Altan
    Trevisan, Maurizio
    D'Agostino, Ralph B., Sr.
    Cooper, Cyrus
    Kavousi, Maryam
    Welin, Lennart
    Roussel, Ronan
    Hu, Frank B.
    Sato, Shinichi
    Davidson, Karina W.
    Howard, Barbara V.
    Leening, Maarten
    Rosengren, Annika
    Dorr, Marcus
    Deeg, Dorly J. H.
    Kiechl, Stefan
    Stehouwer, Coen D. A.
    Nissinen, Aulikki
    Giampaoli, Simona
    Donfrancesco, Chiara
    Kromhout, Daan
    Price, Jackie F.
    Peters, Annette
    Meade, Tom W.
    Casiglia, Edoardo
    Lawlor, Debbie A.
    Gallacher, John
    Nagel, Dorothea
    Franco, Oscar H.
    Assmann, Gerd
    Dagenais, Gilles R.
    Jukema, J. Wouter
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Woodward, Mark
    Brunner, Eric J.
    Khaw, Kay-Tee
    Wareham, Nicholas J.
    Whitsel, Eric A.
    Njolstad, Inger
    Hedblad, Bo
    Wassertheil-Smoller, Sylvia
    Engstrom, Gunnar
    Rosamond, Wayne D.
    Selvin, Elizabeth
    Sattar, Naveed
    Thompson, Simon G.
    Danesh, John
    Association of Cardiometabolic Multimorbidity With Mortality: The Emerging Risk Factors Collaboration2015In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 314, no 1, p. 52-60Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE The prevalence of cardiometabolic multimorbidity is increasing.

    OBJECTIVE To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.

    DESIGN, SETTING, AND PARTICIPANTS Age-and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689 300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128 843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499 808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).

    MAIN OUTCOMES AND MEASURES All-cause mortality and estimated reductions in life expectancy.

    RESULTS In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.

    CONCLUSIONS AND RELEVANCE Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

  • 13. Di Angelantonio, Emanuele
    et al.
    Sarwar, Nadeem
    Perry, Philip
    Kaptoge, Stephen
    Ray, Kausik K
    Thompson, Alexander
    Wood, Angela M
    Lewington, Sarah
    Sattar, Naveed
    Packard, Chris J
    Collins, Rory
    Thompson, Simon G
    Danesh, John
    Major lipids, apolipoproteins, and risk of vascular disease2009In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 302, no 18, p. 1993-2000Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Associations of major lipids and apolipoproteins with the risk of vascular disease have not been reliably quantified.

    OBJECTIVE: To assess major lipids and apolipoproteins in vascular risk.

    DESIGN, SETTING, AND PARTICIPANTS: Individual records were supplied on 302,430 people without initial vascular disease from 68 long-term prospective studies, mostly in Europe and North America. During 2.79 million person-years of follow-up, there were 8857 nonfatal myocardial infarctions, 3928 coronary heart disease [CHD] deaths, 2534 ischemic strokes, 513 hemorrhagic strokes, and 2536 unclassified strokes.

    MAIN OUTCOME MEASURES: Hazard ratios (HRs), adjusted for several conventional factors, were calculated for 1-SD higher values: 0.52 log(e) triglyceride, 15 mg/dL high-density lipoprotein cholesterol (HDL-C), 43 mg/dL non-HDL-C, 29 mg/dL apolipoprotein AI, 29 mg/dL apolipoprotein B, and 33 mg/dL directly measured low-density lipoprotein cholesterol (LDL-C). Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. RESULTS: The rates of CHD per 1000 person-years in the bottom and top thirds of baseline lipid distributions, respectively, were 2.6 and 6.2 with triglyceride, 6.4 and 2.4 with HDL-C, and 2.3 and 6.7 with non-HDL-C. Adjusted HRs for CHD were 0.99 (95% CI, 0.94-1.05) with triglyceride, 0.78 (95% CI, 0.74-0.82) with HDL-C, and 1.50 (95% CI, 1.39-1.61) with non-HDL-C. Hazard ratios were at least as strong in participants who did not fast as in those who did. The HR for CHD was 0.35 (95% CI, 0.30-0.42) with a combination of 80 mg/dL lower non-HDL-C and 15 mg/dL higher HDL-C. For the subset with apolipoproteins or directly measured LDL-C, HRs were 1.50 (95% CI, 1.38-1.62) with the ratio non-HDL-C/HDL-C, 1.49 (95% CI, 1.39-1.60) with the ratio apo B/apo AI, 1.42 (95% CI, 1.06-1.91) with non-HDL-C, and 1.38 (95% CI, 1.09-1.73) with directly measured LDL-C. Hazard ratios for ischemic stroke were 1.02 (95% CI, 0.94-1.11) with triglyceride, 0.93 (95% CI, 0.84-1.02) with HDL-C, and 1.12 (95% CI, 1.04-1.20) with non-HDL-C.

    CONCLUSION: Lipid assessment in vascular disease can be simplified by measurement of either total and HDL cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride.

  • 14. Erqou, Sebhat
    et al.
    Kaptoge, Stephen
    Perry, Philip L
    Di Angelantonio, Emanuele
    Thompson, Alexander
    White, Ian R
    Marcovina, Santica M
    Collins, Rory
    Thompson, Simon G
    Danesh, John
    Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality2009In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 302, no 4, p. 412-423Article in journal (Refereed)
    Abstract [en]

    CONTEXT:

    Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke.

    OBJECTIVE:

    To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes.

    STUDY SELECTION:

    Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators.

    DATA EXTRACTION:

    Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline.

    DATA SYNTHESIS:

    Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer.

    CONCLUSION:

    Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.

  • 15.
    Fazel, Seena
    et al.
    Dept of Psychiatry, University of Oxford, Warneford Hospital, Oxford England.
    Långström, Niklas
    Hjern, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Grann, Martin
    Lichtenstein, Paul
    Schizophrenia, substance abuse, and violent crime2009In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 301, no 19, p. 2016-2023Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Persons with schizophrenia are thought to be at increased risk of committing violent crime 4 to 6 times the level of general population individuals without this disorder. However, risk estimates vary substantially across studies, and considerable uncertainty exists as to what mediates this elevated risk. Despite this uncertainty, current guidelines recommend that violence risk assessment should be conducted for all patients with schizophrenia. OBJECTIVE: To determine the risk of violent crime among patients diagnosed as having schizophrenia and the role of substance abuse in mediating this risk. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal designs were used to link data from nationwide Swedish registers of hospital admissions and criminal convictions in 1973-2006. Risk of violent crime in patients after diagnosis of schizophrenia (n = 8003) was compared with that among general population controls (n = 80 025). Potential confounders (age, sex, income, and marital and immigrant status) and mediators (substance abuse comorbidity) were measured at baseline. To study familial confounding, we also investigated risk of violence among unaffected siblings (n = 8123) of patients with schizophrenia. Information on treatment was not available. MAIN OUTCOME MEASURE: Violent crime (any criminal conviction for homicide, assault, robbery, arson, any sexual offense, illegal threats, or intimidation). RESULTS: In patients with schizophrenia, 1054 (13.2%) had at least 1 violent offense compared with 4276 (5.3%) of general population controls (adjusted odds ratio [OR], 2.0; 95% confidence interval [CI], 1.8-2.2). The risk was mostly confined to patients with substance abuse comorbidity (of whom 27.6% committed an offense), yielding an increased risk of violent crime among such patients (adjusted OR, 4.4; 95% CI, 3.9-5.0), whereas the risk increase was small in schizophrenia patients without substance abuse comorbidity (8.5% of whom had at least 1 violent offense; adjusted OR, 1.2; 95% CI, 1.1-1.4; P<.001 for interaction). The risk increase among those with substance abuse comorbidity was significantly less pronounced when unaffected siblings were used as controls (28.3% of those with schizophrenia had a violent offense compared with 17.9% of their unaffected siblings; adjusted OR, 1.8; 95% CI, 1.4-2.4; P<.001 for interaction), suggesting significant familial (genetic or early environmental) confounding of the association between schizophrenia and violence. CONCLUSIONS: Schizophrenia was associated with an increased risk of violent crime in this longitudinal study. This association was attenuated by adjustment for substance abuse, suggesting a mediating effect. The role of risk assessment, management, and treatment in individuals with comorbidity needs further examination.

  • 16. Hallan, Stein I
    et al.
    Matsushita, Kunihiro
    Sang, Yingying
    Mahmoodi, Bakhtawar K
    Black, Corri
    Ishani, Areef
    Kleefstra, Nanne
    Naimark, David
    Roderick, Paul
    Tonelli, Marcello
    Wetzels, Jack F M
    Astor, Brad C
    Gansevoort, Ron T
    Levin, Adeera
    Wen, Chi-Pang
    Coresh, Josef
    Age and association of kidney measures with mortality and end-stage renal disease.2012In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 308, no 22, p. 2349-60Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial.

    OBJECTIVE: To evaluate possible effect modification (interaction) by age of the association of eGFR and albuminuria with clinical risk, examining both relative and absolute risks.

    DESIGN, SETTING, AND PARTICIPANTS: Individual-level meta-analysis including 2,051,244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD cohorts from Asia, Australasia, Europe, and North/South America, conducted in 1972-2011 with a mean follow-up time of 5.8 years (range, 0-31 years).

    MAIN OUTCOME MEASURES: Hazard ratios (HRs) of mortality and end-stage renal disease (ESRD) according to eGFR and albuminuria were meta-analyzed across age categories after adjusting for sex, race, cardiovascular disease, diabetes, systolic blood pressure, cholesterol, body mass index, and smoking. Absolute risks were estimated using HRs and average incidence rates.

    RESULTS: Mortality (112,325 deaths) and ESRD (8411 events) risks were higher at lower eGFR and higher albuminuria in every age category. In general and high-risk cohorts, relative mortality risk for reduced eGFR decreased with increasing age; eg, adjusted HRs at an eGFR of 45 mL/min/1.73 m2 vs 80 mL/min/1.73 m2 were 3.50 (95% CI, 2.55-4.81), 2.21 (95% CI, 2.02-2.41), 1.59 (95% CI, 1.42-1.77), and 1.35 (95% CI, 1.23-1.48) in age categories 18-54, 55-64, 65-74, and ≥75 years, respectively (P <.05 for age interaction). Absolute risk differences for the same comparisons were higher at older age (9.0 [95% CI, 6.0-12.8], 12.2 [95% CI, 10.3-14.3], 13.3 [95% CI, 9.0-18.6], and 27.2 [95% CI, 13.5-45.5] excess deaths per 1000 person-years, respectively). For increased albuminuria, reduction of relative risk with increasing age was less evident, while differences in absolute risk were higher in older age categories (7.5 [95% CI, 4.3-11.9], 12.2 [95% CI, 7.9-17.6], 22.7 [95% CI, 15.3-31.6], and 34.3 [95% CI, 19.5-52.4] excess deaths per 1000 person-years, respectively by age category, at an albumin-creatinine ratio of 300 mg/g vs 10 mg/g). In CKD cohorts, adjusted relative hazards of mortality did not decrease with age. In all cohorts, ESRD relative risks and absolute risk differences at lower eGFR or higher albuminuria were comparable across age categories.

    CONCLUSIONS: Both low eGFR and high albuminuria were independently associated with mortality and ESRD regardless of age across a wide range of populations. Mortality showed lower relative risk but higher absolute risk differences at older age.

  • 17.
    Hammel, Pascal
    et al.
    Hop Beaujon, AP HP, Dept Digest Oncol, F-92110 Clichy, France..
    Huguet, Florence
    Tenon Hosp, AP HP, Dept Radiotherapy, Paris, France..
    van Laethem, Jean-Luc
    Erasme Univ Hosp, Dept Gastroenterol, B-1070 Brussels, Belgium..
    Goldstein, David
    Prince Wales Hosp, Dept Med Oncol, Sydney, NSW, Australia.;Australasian Gastrointestinal Trials Grp AGITG, Camperdown, NSW, Australia.;Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW, Australia..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Artru, Pascal
    Jean Mermoz Hosp, Dept Gastroenterol, Lyon, France..
    Borbath, Ivan
    Clin Univ St Luc, Dept Gastroenterol, B-1200 Brussels, Belgium..
    Bouche, Olivier
    Hop Robert Debre, Dept Gastroenterol, Reims, France..
    Shannon, Jenny
    Australasian Gastrointestinal Trials Grp AGITG, Camperdown, NSW, Australia.;Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW, Australia.;Nepean Hosp NSW, Dept Med Oncol, Sydney, NSW, Australia..
    Andre, Thierry
    Hop St Antoine, AP HP, Dept Med Oncol, F-75571 Paris, France..
    Mineur, Laurent
    St Catherine Inst, Dept Radiotherapy & Med Oncol, Avignon, France..
    Chibaudel, Benoist
    Franco British Hosp Inst, Dept Med Oncol, Levallois Perret, France.;Oncol Multidisciplinary Res Grp GERCOR, Paris, France..
    Bonnetain, Franck
    Hosp Minjoz, Dept Methodol & Qual Life Oncol, Besancon, France..
    Louvet, Christophe
    Inst Mutualiste Montsouris, Dept Med Oncol, Paris, France..
    Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial2016In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 315, no 17, p. 1844-1853Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE In locally advanced pancreatic cancer, the role of chemoradiotherapy is controversial and the efficacy of erlotinib is unknown.

    OBJECTIVES To assess whether chemoradiotherapy improves overall survival of patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine-based induction chemotherapy and to assess the effect of erlotinib on survival.

    DESIGN, SETTING, AND PARTICIPANTS InLAP07, an international, open-label, phase3randomized trial, 449 patientswere enrolled between 2008and 2011. Follow-up ended in February 2013.

    INTERVENTIONS In the first randomization, 223 patients received 1000mg/m(2) weekly of gemcitabine alone and 219 patients received 1000mg/m(2) of gemcitabine plus 100mg/d of erlotinib. In the second randomization involving patients with progression-free disease after 4 months, 136 patients received 2 months of the same chemotherapy and 133 underwent chemoradiotherapy (54 Gy plus capecitabine).

    MAIN OUTCOMES AND MEASURES The primary outcomewas overall survival from the date of the first randomization. Secondary outcomeswere the effect of erlotinib and quality assurance of radiotherapy on overall survival, progression-free survival of gemcitabine-erlotinib and erlotinib maintenance with gemcitabine alone at the second randomization, and toxic effects.

    RESULTS A total of 442 of the 449 patients (232 men; median age, 63.3 years) enrolled underwent the first randomization. Of these, 269 underwent the second randomization. Interim analysis was performed when 221 patients died (109 in the chemoradiotherapy group and 112 in the chemotherapy group), reaching the early stopping boundaries for futility. With a median follow-up of 36.7 months, the median overall survival from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5-18.5 months) and chemoradiotherapy at 15.2 months (95% CI, 13.9-17.3 months; hazard ratio [HR], 1.03; 95% CI, 0.79-1.34; P = .83). Median overall survival from the date of the first randomization for the 223 patients receiving gemcitabine was 13.6 months (95% CI, 12.3-15.3 months) and was 11.9 months (95% CI, 10.4-13.5 months) for the 219 patients receiving gemcitabine plus erlotinib (HR, 1.19; 95% CI, 0.97-1.45; P = .09; 188 deaths vs 191 deaths). Chemoradiotherapy was associated with decreased local progression (32% vs 46%, P = .03) and no increase in grade 3 to 4 toxicity, except for nausea.

    CONCLUSIONS AND RELEVANCE In this open-label, randomized trial involving patients with locally advanced pancreatic cancer with disease controlled after 4 months of induction chemotherapy, there was no significant difference in overall survival with chemoradiotherapy compared with chemotherapy alone and there was no significant difference in overall survival with gemcitabine compared with gemcitabine plus erlotinib used as maintenance therapy.

  • 18.
    Ingelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Björklund-Bodegård, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Diurnal blood pressure pattern and risk of congestive heart failure2006In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 295, no 24, p. 2859-2866Article in journal (Refereed)
    Abstract [en]

    CONTEXT: High blood pressure is the most important risk factor for congestive heart failure (CHF) at a population level, but the relationship of an altered diurnal blood pressure pattern to risk of subsequent CHF is unknown.

    OBJECTIVES: To explore 24-hour ambulatory blood pressure characteristics as predictors of CHF incidence and to investigate whether altered diurnal blood pressure patterns confer any additional risk information beyond that provided by conventional office blood pressure measurements.

    DESIGN, SETTING, AND PARTICIPANTS: Prospective, community-based, observational cohort in Uppsala, Sweden, including 951 elderly men free of CHF, valvular disease, and left ventricular hypertrophy at baseline between 1990 and 1995, followed up until the end of 2002. Twenty-four-hour ambulatory blood pressure monitoring was performed at baseline, and the blood pressure variables were analyzed as predictors of subsequent CHF.

    MAIN OUTCOME MEASURE: First hospitalization for CHF.

    RESULTS: Seventy men developed heart failure during follow-up, with an incidence rate of 8.6 per 1000 person-years at risk. In multivariable Cox proportional hazards models adjusted for antihypertensive treatment and established risk factors for CHF (myocardial infarction, diabetes, smoking, body mass index, and serum cholesterol level), a 1-SD (9-mm Hg) increase in nighttime ambulatory diastolic blood pressure (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.02-1.55) and the presence of "nondipping" blood pressure (night-day ambulatory blood pressure ratio > or =1; HR, 2.29; 95% CI, 1.16-4.52) were associated with an increased risk of CHF. After adjusting for office-measured systolic and diastolic blood pressures, nondipping blood pressure remained a significant predictor of CHF (HR, 2.21; 95% CI, 1.12-4.36 vs normal night-day pattern). Nighttime ambulatory diastolic blood pressure and nondipping blood pressure were also significant predictors of CHF after exclusion of all participants who had an acute myocardial infarction before baseline or during follow-up.

    CONCLUSIONS: Nighttime blood pressure appears to convey additional risk information about CHF beyond office-measured blood pressure and other established risk factors for CHF. The clinical value of this association remains to be established in future studies.

  • 19.
    Ingelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Frystyk, Jan
    Flyvbjerg, Allan
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Adiponectin and risk of congestive heart failure2006In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 295, no 15, p. 1772-1774Article in journal (Refereed)
  • 20.
    Ingelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Insulin resistance and risk of congestive heart failure2005In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 294, no 3, p. 334-41Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Diabetes and obesity are established risk factors for congestive heart failure (CHF) and are both associated with insulin resistance. OBJECTIVE: To explore if insulin resistance may predict CHF and may provide the link between obesity and CHF. DESIGN, SETTING, AND PARTICIPANTS: The Uppsala Longitudinal Study of Adult Men, a prospective, community-based, observational cohort in Uppsala, Sweden. We investigated 1187 elderly (>or=70 years) men free from CHF and valvular disease at baseline between 1990 and 1995, with follow-up until the end of 2002. Variables reflecting insulin sensitivity (including euglycemic insulin clamp glucose disposal rate) and obesity were analyzed together with established risk factors (prior myocardial infarction, hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, and serum cholesterol level) as predictors of subsequent incidence of CHF, using Cox proportional hazards analyses. MAIN OUTCOME MEASURE: First hospitalization for heart failure. RESULTS: One hundred four men developed CHF during a median follow-up of 8.9 (range, 0.01-11.4) years. In multivariable Cox proportional hazards models adjusted for established risk factors for CHF, increased risk of CHF was associated with a 1-SD increase in the 2-hour glucose value of an oral glucose tolerance test (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.08-1.93), fasting serum proinsulin level (HR, 1.29; 95% CI, 1.02-1.64), body mass index (HR, 1.35; 95% CI, 1.11-1.65), and waist circumference (HR, 1.36; 95% CI, 1.10-1.69), whereas a 1-SD increase in clamp glucose disposal rate decreased the risk (HR, 0.66; 95% CI, 0.51-0.86). When adding clamp glucose disposal rate to these models as a covariate, the obesity variables were no longer significant predictors of subsequent CHF. CONCLUSIONS: Insulin resistance predicted CHF incidence independently of established risk factors including diabetes in our large community-based sample of elderly men. The previously described association between obesity and subsequent CHF may be mediated largely by insulin resistance.

  • 21. Jaffe, Allan S.
    et al.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Katus, Hugo A.
    Sensitive Troponin I Assay in Patients With Suspected Acute Coronary Syndrome2011In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 306, no 5, p. 488-489Article in journal (Refereed)
  • 22. Jernberg, Tomas
    et al.
    Johanson, Per
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Svennblad, Bodil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Association Between Adoption of Evidence-Based Treatment and Survival for Patients With ST-Elevation Myocardial Infarction2011In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 305, no 16, p. 1677-1684Article in journal (Refereed)
    Abstract [en]

    Context Only limited information is available on the speed of implementation of new evidence-based and guideline-recommended treatments and its association with survival in real life health care of patients with ST-elevation myocardial infarction (STEMI). Objective To describe the adoption of new treatments and the related chances of short-and long-term survival in consecutive patients with STEMI in a single country over a 12-year period. Design, Setting, and Participants The Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA) records baseline characteristics, treatments, and outcome of consecutive patients with acute coronary syndrome admitted to almost all hospitals in Sweden. This study includes 61 238 patients with a first-time diagnosis of STEMI between 1996 and 2007. Main Outcome Measures Estimated and crude proportions of patients treated with different medications and invasive procedures and mortality over time. Results Of evidence based-treatments, reperfusion increased from 66% (95%, confidence interval [CI], 52%-79%) to 79% (95% CI, 69%-89%; P<.001), primary percutaneous coronary intervention from 12% (95% CI, 11%-14%) to 61% (95% CI, 45%-77%; P<.001), and revascularization from 10% (96% CI, 6%-14%) to 84% (95% CI, 73%-95%; P<.001). The use of aspirin, clopidogrel, beta-blockers, statins, and angiotensin-converting enzyme (ACE) inhibitors all increased: clopidogrel from 0% to 82% (95% CI, 69%-95%; P<.001), statins from 23% (95% CI, 12%-33%) to 83% (95% CI, 75%-91%; P<.001), and ACE inhibitor or angiotensin II receptor blockers from 39% (95% CI, 26%-52%) to 69% (95% CI, 58%-70%; P<.001). The estimated in-hospital, 30-day and 1-year mortality decreased from 12.5% (95% CI, 4.3%-20.6%) to 7.2% (95% CI, 1.7%-12.6%; P<.001); from 15.0% (95% CI, 6.2%-23.7%) to 8.6% (95% CI, 2.7%-14.5%; P<.001); and from 21.0% (95% CI, 11.0%-30.9%) to 13.3% (95% CI, 6.0%-20.4%; P<.001), respectively. After adjustment, there was still a consistent trend with lower standardized mortality over the years. The 12-year survival analyses showed that the decrease of mortality was sustained over time. Conclusion In a Swedish registry of patients with STEMI, between 1996 and 2007, there was an increase in the prevalence of evidence-based treatments. During this same time, there was a decrease in 30-day and 1-year mortality that was sustained during long-term follow-up.

  • 23. Jernberg, Tomas
    et al.
    Johanson, Per
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Evidence-Based Treatment and ST-Segment Elevation Myocardial Infarction Reply2011In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 306, no 7, p. 707-708Article in journal (Refereed)
  • 24.
    Jobs, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Nerpin, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Jobs, Magnus
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Association Between Serum Cathepsin S and Mortality in Older Adults2011In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 306, no 10, p. 1113-1121Article in journal (Refereed)
    Abstract [en]

    Context: Experimental data suggest that cathepsin S, a cysteine protease, is involved in the complex pathways leading to cardiovascular disease and cancer. However, prospective data concerning a potential association between circulating cathepsin S levels and mortality are lacking.

    Objective: To investigate associations between circulating cathepsin S levels and mortality in 2 independent cohorts of elderly men and women.

    Design, Setting, and Participants: Prospective study using 2 community-based cohorts, the Uppsala Longitudinal Study of Adult Men (ULSAM; n=1009; mean age: 71 years; baseline period: 1991-1995; median follow-up: 12.6 years; end of follow-up: 2006) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n=987; 50% women; mean age: 70 years; baseline period: 2001-2004; median follow-up: 7.9 years; end of follow-up: 2010). Serum samples were used to measure cathepsin S.

    Main Outcome Measure: Total mortality.

    Results: During follow-up, 413 participants died in the ULSAM cohort (incidence rate: 3.59/100 person-years at risk) and 100 participants died in the PIVUS cohort (incidence rate: 1.32/100 person-years at risk). In multivariable Cox regression models adjusted for age, systolic blood pressure, diabetes, smoking status, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease, higher serum cathepsin S was associated with an increased risk for mortality (ULSAM cohort: hazard ratio [HR] for 1-unit increase of cathepsin S, 1.04 [95% CI, 1.01-1.06], P=.009; PIVUS cohort: HR for 1-unit increase of cathepsin S, 1.03 [95% CI, 1.00-1.07], P=.04). In the ULSAM cohort, serum cathepsin S also was associated with cardiovascular mortality (131 deaths; HR for quintile 5 vs quintiles 1-4, 1.62 [95% CI, 1.11-2.37]; P=.01) and cancer mortality (148 deaths; HR for 1-unit increase of cathepsin S, 1.05 [95% CI, 1.01-1.10]; P=.01).

    Conclusions: Among elderly individuals in 2 independent cohorts, higher serum cathepsin S levels were associated with increased mortality risk. Additional research is needed to delineate the role of cathepsin S and whether its measurement might have clinical utility.

  • 25. Johansson, Jan-Erik
    et al.
    Andrén, Ove
    Andersson, Swen-Olof
    Dickman, Paul W.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Magnuson, Anders
    Adami, Hans-Olov
    Natural history of early, localized prostate cancer2004In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 291, no 22, p. 2713-2719Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Among men with early prostate cancer, the natural history without initial therapy determines the potential for survival benefit following radical local treatment. However, little is known about disease progression and mortality beyond 10 to 15 years of watchful waiting. OBJECTIVE: To examine the long-term natural history of untreated, early stage prostatic cancer. DESIGN: Population-based, cohort study with a mean observation period of 21 years. SETTING: Regionally well-defined catchment area in central Sweden (recruitment March 1977 through February 1984). PATIENTS: A consecutive sample of 223 patients (98% of all eligible) with early-stage (T0-T2 NX M0 classification), initially untreated prostatic cancer. Patients with tumor progression were hormonally treated (either by orchiectomy or estrogens) if they had symptoms. MAIN OUTCOME MEASURES: Progression-free, cause-specific, and overall survival. RESULTS: After complete follow-up, 39 (17%) of all patients experienced generalized disease. Most cancers had an indolent course during the first 10 to 15 years. However, further follow-up from 15 (when 49 patients were still alive) to 20 years revealed a substantial decrease in cumulative progression-free survival (from 45.0% to 36.0%), survival without metastases (from 76.9% to 51.2%), and prostate cancer-specific survival (from 78.7% to 54.4%). The prostate cancer mortality rate increased from 15 per 1000 person-years (95% confidence interval, 10-21) during the first 15 years to 44 per 1000 person-years (95% confidence interval, 22-88) beyond 15 years of follow-up (P =.01). CONCLUSION: Although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. These findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.

  • 26. Johansson, Jan-Erik
    et al.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Johansson, Sara
    Bergström, Reinhold
    Adami, Hans-Olov
    Fifteen-year survival in prostate cancer: a prospective, population-based study in Sweden1997In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 277, no 6, p. 467-471Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To describe the natural history of initially untreated early-stage prostate cancer. A key secondary objective was to calculate long-term survival rates by stage, grade, and age at diagnosis. DESIGN: Prospective cohort study. SETTING: Population-based in 1 county of Sweden, without screening for prostate cancer. PATIENTS: A group of 642 patients with prostate cancer of any stage, consecutively diagnosed between 1977 and 1984 at a mean age of 72 years with complete follow-up to 1994. MAIN OUTCOME MEASURES: Proportion of patients who died from prostate cancer, and 15-year survival (with 95% confidence interval [CI]), corrected for causes of death other than prostate cancer. RESULTS: In the entire cohort, prostate cancer accounted for 201 (37%) of all 541 deaths. Among 300 patients with a diagnosis of localized disease (T0-T2), 33 (11%) died of prostate cancer. In this group, the corrected 15-year survival rate was similar in 223 patients with deferred treatment (81%; 95% CI, 72%-89%) and in 77 who received initial treatment (81%; 95% CI, 67%-95%). The corrected 15-year survival was 57% (95% CI, 45%-68%) in 183 patients with locally advanced cancer (T3-T4) and 6% (95% CI, 0%-12%) in those 159 who had distant metastases at the time of diagnosis. CONCLUSION: Patients with localized prostate cancer have a favorable outlook following watchful waiting, and the number of deaths potentially avoidable by radical initial treatment is limited. Without reliable prognostic indicators, an aggressive approach to all patients with early disease would entail substantial overtreatment. In contrast, patients with locally advanced or metastatic disease need trials of aggressive therapy to improve their poor prognosis.

  • 27.
    Larsson, Susanna C.
    et al.
    Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, SE-17177 Stockholm, Sweden..
    Burgess, Stephen
    Univ Cambridge, MRC Biostat Unit, Cambridge, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction2017In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 318, no 4, p. 371-380Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction.

    OBJECTIVE To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization.

    DESIGN, SETTING, AND PARTICIPANTS The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide association meta-analysis of serum calcium levels (N = up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium's 1000 genomes-based genome-wide association meta-analysis (N = up to 184 305 individuals) that included cases (individuals with CAD andmyocardial infarction) and noncases, with baseline data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD andmyocardial infarction was weighted by its association with serum calcium, and estimates were combined using an inverse-variance weighted meta-analysis.

    EXPOSURES Genetic risk score based on genetic variants related to elevated serum calcium levels.

    MAIN OUTCOMES AND MEASURES Co-primary outcomes were the odds of CAD and myocardial infarction.

    RESULTS Among the mendelian randomized analytic sample of 184 305 individuals (60 801 CAD cases [approximately 70% with myocardial infarction] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weighted meta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically predicted serum calcium levels were 1.25 (95% CI, 1.08-1.45; P = .003) for CAD and 1.24 (95% CI, 1.05-1.46; P = .009) for myocardial infarction.

    CONCLUSIONS AND RELEVANCE A genetic predisposition to higher serum calcium levels was associated with increased risk of CAD andmyocardial infarction. Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medium-term calcium supplementation is unknown.

  • 28. Levin, G. P.
    et al.
    Robinson-Cohen, C.
    De Boer, I. H.
    Houston, D. K.
    Lohman, K.
    Liu, Y.
    Kritchevsky, S. B.
    Cauley, J. A.
    Tanaka, T.
    Ferrucci, L.
    Bandinelli, S.
    Patel, K. V.
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wang, T.
    Wolf, M.
    Psaty, B. M.
    Siscovick, D.
    Kestenbaum, B.
    Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes2012In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 308, no 18, p. 1898-1905Article in journal (Refereed)
    Abstract [en]

    Context Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.

    Objective To investigate whether common variation within genes encoding the vitamin D–binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.

    Design, Setting, and Participants Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.

    Main Outcome Measure Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.

    Results Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.

    Conclusion Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

  • 29.
    Lind, Marcus
    et al.
    Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden.;NU Hosp Grp, Dept Med, Uddevalla, Sweden..
    Polonsky, William
    Univ Calif San Diego, La Jolla, CA 92093 USA..
    Hirsch, Irl B.
    Univ Washington, Sch Med, Seattle, WA USA..
    Heise, Tim
    Profil, Neuss, Germany..
    Bolinder, Jan
    Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Dahlqvist, Sofia
    NU Hosp Grp, Dept Med, Uddevalla, Sweden..
    Schwarz, Erik
    Univ Orebro, Fac Med & Hlth, Dept Internal Med, Orebro, Sweden..
    Olafsdottir, Arndis Finna
    NU Hosp Grp, Dept Med, Uddevalla, Sweden..
    Frid, Anders
    Skane Univ Hosp, Dept Clin Sci, Div Endocrinol, Malmo, Sweden.;Lund Univ, Lund, Sweden..
    Wedel, Hans
    Univ Gothenburg, Hlth Metr Sahlgrenska Acad, Gothenburg, Sweden..
    Ahlen, Elsa
    Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden.;NU Hosp Grp, Dept Med, Uddevalla, Sweden..
    Nystrom, Thomas
    Karolinska Inst, Sodersjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden..
    Hellman, Jarl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Continuous Glucose Monitoring vs Conventional Therapy for Glycemic Control in Adults With Type 1 Diabetes Treated With Multiple Daily Insulin Injections The GOLD Randomized Clinical Trial2017In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 317, no 4, p. 379-387Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE The majority of individuals with type 1 diabetes do not meet recommended glycemic targets. OBJECTIVE To evaluate the effects of continuous glucose monitoring in adults with type 1 diabetes treated with multiple daily insulin injections. DESIGN, SETTING, AND PARTICIPANTS Open-label crossover randomized clinical trial conducted in 15 diabetes outpatient clinics in Sweden between February 24, 2014, and June 1, 2016 that included 161 individuals with type 1 diabetes and hemoglobin A(1c) (HbA(1c)) of at least 7.5%(58 mmol/mol) treated with multiple daily insulin injections. INTERVENTIONS Participants were randomized to receive treatment using a continuous glucose monitoring system or conventional treatment for 26 weeks, separated by a washout period of 17 weeks. MAIN OUTCOMES AND MEASURES Difference in HbA(1c) between weeks 26 and 69 for the 2 treatments. Adverse events including severe hypoglycemia were also studied. RESULTS Among 161 randomized participants, mean age was 43.7 years, 45.3% were women, and mean HbA(1c) was 8.6%(70 mmol/mol). A total of 142 participants had follow-up data in both treatment periods. Mean HbA(1c) was 7.92%(63 mmol/mol) during continuous glucose monitoring use and 8.35%(68 mmol/mol) during conventional treatment (mean difference, -0.43% [95% CI, -0.57% to -0.29%] or -4.7 [-6.3 to -3.1 mmol/mol]; P < .001). Of 19 secondary end points comprising psychosocial and various glycemic measures, 6 met the hierarchical testing criteria of statistical significance, favoring continuous glucose monitoring compared with conventional treatment. Five patients in the conventional treatment group and 1 patient in the continuous glucose monitoring group had severe hypoglycemia. During washout when patients used conventional therapy, 7 patients had severe hypoglycemia. CONCLUSIONS AND RELEVANCE Among patients with inadequately controlled type 1 diabetes treated with multiple daily insulin injections, the use of continuous glucose monitoring compared with conventional treatment for 26 weeks resulted in lower HbA(1c). Further research is needed to assess clinical outcomes and longer-term adverse effects.

  • 30. Loeb, Stacy
    et al.
    Folkvaljon, Yasin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lambe, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Robinson, David
    Garmo, Hans
    Ingvar, Christian
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma2015In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 313, no 24, p. 2449-2455Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE The target for the oral erectile dysfunction drugs, phosphodiesterase type 5 (PDE5) inhibitors, is part of a pathway implicated in the development of malignant melanoma. An increased risk of melanoma in sildenafil users was recently reported. OBJECTIVE To examine the association between use of PDE5 inhibitors and melanoma risk, including data on specific PDE5 inhibitors, number of prescriptions, and melanoma stage. DESIGN, SETTING, AND PARTICIPANTS Nationwide, population-based, nested case-control study in the Swedish Prescribed Drug Register, the Swedish Melanoma Register, and other health care registers and demographic databases in Sweden, including 4065 melanoma cases diagnosed from 2006 through 2012 and 5 randomly selected controls per case with matching year of birth. EXPOSURES Number of filled prescriptions for the PDE5 inhibitors sildenafil and vardenafil or tadalafil. MAIN OUTCOMES AND MEASURES Risk of melanoma; overall and by stage and risk of basal cell carcinoma in multivariable logistic regression analyses. RESULTS Of 4065 melanoma cases, 435 men (11%) had filled prescriptions for PDE5 inhibitors, as did 1713 men of 20 325 controls (8%). In multivariable analysis, there was an increased risk of melanoma in men taking PDE5 inhibitors (OR, 1.21 [95% CI, 1.08-1.36]). The most pronounced increase in risk was observed in men who had filled a single prescription (OR, 1.32 [95% CI, 1.10-1.59]; exposure rate, 4% for cases vs 3% for controls), but was not significant among men with multiple filled prescriptions (for 2-5 prescriptions: OR, 1.14 [95% CI, 0.95-1.37], 4% for cases and 3% for controls; for >= 6 prescriptions: OR, 1.17 [95% CI, 0.95-1.44], 3% for cases vs 2% for controls). PDE5 inhibitors were significantly associated with melanoma stage 0 (OR, 1.49 [95% CI, 1.22-1.83], 13% for cases vs 8% for controls) and stage I (OR, 1.21 [95% CI, 1.02-1.43], 12% for cases vs 10% for controls), but not stage II through IV (OR, 0.83 [95% CI, 0.63-1.09], 6% for cases vs 7% for controls). The risk estimates were similar for sildenafil and vardenafil or tadalafil. PDE5 inhibitor use was also associated with an increased risk of basal cell carcinoma (OR, 1.19 [95% CI, 1.14-1.25], 9% for cases vs 8% for controls). Men taking PDE5 inhibitors had a higher educational level and annual income, factors that were also significantly associated with melanoma risk. CONCLUSIONS AND RELEVANCE In a Swedish cohort of men, the use of PDE5 inhibitors was associated with a modest but statistically significant increased risk of malignant melanoma. However, the pattern of association (eg, the lack of association with multiple filled prescriptions) raises questions about whether this association is causal.

  • 31.
    Lundin, Stefan
    et al.
    Sahlgrens Univ Hosp, Dept Anesthesiol & Intens Care, Gothenburg, Sweden.
    Persson, Per
    Sahlgrens Univ Hosp, Dept Anesthesiol & Intens Care, Gothenburg, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Strategies to Adjust Positive End-Expiratory Pressure in Patients With ARDS2019In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 322, no 6, p. 581-581Article in journal (Other academic)
  • 32. Matsushita, Kunihiro
    et al.
    Mahmoodi, Bakhtawar K
    Woodward, Mark
    Emberson, Jonathan R
    Jafar, Tazeen H
    Jee, Sun Ha
    Polkinghorne, Kevan R
    Shankar, Anoop
    Smith, David H
    Tonelli, Marcello
    Warnock, David G
    Wen, Chi-Pang
    Coresh, Josef
    Gansevoort, Ron T
    Hemmelgarn, Brenda R
    Levey, Andrew S
    Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate2012In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 307, no 18, p. 1941-1951Article in journal (Refereed)
    Abstract [en]

    CONTEXT:

    The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation more accurately estimates glomerular filtration rate (GFR) than the Modification of Diet in Renal Disease (MDRD) Study equation using the same variables, especially at higher GFR, but definitive evidence of its risk implications in diverse settings is lacking.

    OBJECTIVE:

    To evaluate risk implications of estimated GFR using the CKD-EPI equation compared with the MDRD Study equation in populations with a broad range of demographic and clinical characteristics.

    DESIGN, SETTING, AND PARTICIPANTS:

    A meta-analysis of data from 1.1 million adults (aged ≥ 18 years) from 25 general population cohorts, 7 high-risk cohorts (of vascular disease), and 13 CKD cohorts. Data transfer and analyses were conducted between March 2011 and March 2012.

    MAIN OUTCOME MEASURES:

    All-cause mortality (84,482 deaths from 40 cohorts), cardiovascular mortality (22,176 events from 28 cohorts), and end-stage renal disease (ESRD) (7644 events from 21 cohorts) during 9.4 million person-years of follow-up; the median of mean follow-up time across cohorts was 7.4 years (interquartile range, 4.2-10.5 years).

    RESULTS:

    Estimated GFR was classified into 6 categories (≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2) by both equations. Compared with the MDRD Study equation, 24.4% and 0.6% of participants from general population cohorts were reclassified to a higher and lower estimated GFR category, respectively, by the CKD-EPI equation, and the prevalence of CKD stages 3 to 5 (estimated GFR <60 mL/min/1.73 m2) was reduced from 8.7% to 6.3%. In estimated GFR of 45 to 59 mL/min/1.73 m2 by the MDRD Study equation, 34.7% of participants were reclassified to estimated GFR of 60 to 89 mL/min/1.73 m2 by the CKD-EPI equation and had lower incidence rates (per 1000 person-years) for the outcomes of interest (9.9 vs 34.5 for all-cause mortality, 2.7 vs 13.0 for cardiovascular mortality, and 0.5 vs 0.8 for ESRD) compared with those not reclassified. The corresponding adjusted hazard ratios were 0.80 (95% CI, 0.74-0.86) for all-cause mortality, 0.73 (95% CI, 0.65-0.82) for cardiovascular mortality, and 0.49 (95% CI, 0.27-0.88) for ESRD. Similar findings were observed in other estimated GFR categories by the MDRD Study equation. Net reclassification improvement based on estimated GFR categories was significantly positive for all outcomes (range, 0.06-0.13; all P < .001). Net reclassification improvement was similarly positive in most subgroups defined by age (<65 years and ≥65 years), sex, race/ethnicity (white, Asian, and black), and presence or absence of diabetes and hypertension. The results in the high-risk and CKD cohorts were largely consistent with the general population cohorts.

    CONCLUSION:

    The CKD-EPI equation classified fewer individuals as having CKD and more accurately categorized the risk for mortality and ESRD than did the MDRD Study equation across a broad range of populations.

  • 33.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Soluble RANKL and risk of nontraumatic fracture2004In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 291, no 22, p. 2703-4Article in journal (Refereed)
  • 34.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vitamin E supplements an immune response in elderly patients1997In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 279, no 7, p. 505-6Article in journal (Refereed)
  • 35.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hermansson, Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Controversies: treatment of acute otitis media1998In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 279, no 22, p. 1783-4; author reply 1785Article in journal (Refereed)
  • 36.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Cardiovascular Disease, Hypertension, and Risk of Hip Fracture: Reply2010In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 303, no 8, p. 731-732Article in journal (Refereed)
  • 37. Neoptolemos, John P.
    et al.
    Moore, Malcolm J.
    Cox, Trevor F.
    Valle, Juan W.
    Palmer, Daniel H.
    McDonald, Alexander C.
    Carter, Ross
    Tebbutt, Niall C.
    Dervenis, Christos
    Smith, David
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Charnley, Richard M.
    Lacaine, Francois
    Scarfe, Andrew G.
    Middleton, Mark R.
    Anthoney, Alan
    Ghaneh, Paula
    Halloran, Christopher M.
    Lerch, Markus M.
    Olah, Attila
    Rawcliffe, Charlotte L.
    Verbeke, Caroline S.
    Campbell, Fiona
    Buechler, Markus W.
    Effect of Adjuvant Chemotherapy With Fluorouracil Plus Folinic Acid or Gemcitabine vs Observation on Survival in Patients With Resected Periampullary Adenocarcinoma: The ESPAC-3 Periampullary Cancer Randomized Trial2012In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 308, no 2, p. 147-156Article in journal (Refereed)
    Abstract [en]

    Context  Patients with periampullary adenocarcinomas undergo the same resectional surgery as that of patients with pancreatic ductal adenocarcinoma. Although adjuvant chemotherapy has been shown to have a survival benefit for pancreatic cancer, there have been no randomized trials for periampullary adenocarcinomas.

    Objective  To determine whether adjuvant chemotherapy (fluorouracil or gemcitabine) provides improved overall survival following resection.

    Design, Setting, and Patients  The European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary trial, an open-label, phase 3, randomized controlled trial (July 2000-May 2008) in 100 centers in Europe, Australia, Japan, and Canada. Of the 428 patients included in the primary analysis, 297 had ampullary, 96 had bile duct, and 35 had other cancers.

    Interventions  One hundred forty-four patients were assigned to the observation group, 143 patients to receive 20 mg/m2 of folinic acid via intravenous bolus injection followed by 425 mg/m2 of fluorouracil via intravenous bolus injection administered 1 to 5 days every 28 days, and 141 patients to receive 1000 mg/m2 of intravenous infusion of gemcitabine once a week for 3 of every 4 weeks for 6 months.

    Main Outcome Measures  The primary outcome measure was overall survival with chemotherapy vs no chemotherapy; secondary measures were chemotherapy type, toxic effects, progression-free survival, and quality of life.

    Results  Eighty-eight patients (61%) in the observation group, 83 (58%) in the fluorouracil plus folinic acid group, and 73 (52%) in the gemcitabine group died. In the observation group, the median survival was 35.2 months (95%% CI, 27.2-43.0 months) and was 43.1 (95%, CI, 34.0-56.0) in the 2 chemotherapy groups (hazard ratio, 0.86; (95% CI, 0.66-1.11; χ2 = 1.33; P = .25). After adjusting for independent prognostic variables of age, bile duct cancer, poor tumor differentiation, and positive lymph nodes and after conducting multiple regression analysis, the hazard ratio for chemotherapy compared with observation was 0.75 (95% CI, 0.57-0.98; Wald χ2 = 4.53, P = .03).

    Conclusions  Among patients with resected periampullary adenocarcinoma, adjuvant chemotherapy, compared with observation, was not associated with a significant survival benefit in the primary analysis; however, multivariable analysis adjusting for prognostic variables demonstrated a statistically significant survival benefit associated with adjuvant chemotherapy.

  • 38.
    Norman, Mikael
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Pediat, Stockholm, Sweden;Karolinska Univ Hosp, Dept Neonatal Med, Stockholm, Sweden;Umea Univ Hosp, Umea, Sweden.
    Hallberg, Boubou
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Pediat, Stockholm, Sweden;Karolinska Univ Hosp, Dept Neonatal Med, Stockholm, Sweden.
    Abrahamsson, Thomas
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Linkoping Univ, Dept Pediat, Linkoping, Sweden.
    Björklund, Lars J.
    Lund Univ, Dept Clin Sci, Lund, Sweden;Lund Univ, Dept Pediat, Lund, Sweden;Skane Univ Hosp, Lund, Sweden.
    Domellöf, Magnus
    Umea Univ, Dept Clin Sci, Umea, Sweden;Umea Univ, Dept Pediat, Umea, Sweden.
    Farooqi, Aijaz
    Umea Univ, Dept Clin Sci, Umea, Sweden;Umea Univ, Dept Pediat, Umea, Sweden.
    Bruun, Cathrine Foyn
    Umea Univ, Dept Clin Sci, Umea, Sweden;Umea Univ, Dept Pediat, Umea, Sweden.
    Gadsboll, Christian
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Linkoping Univ, Dept Pediat, Linkoping, Sweden;Lund Univ, Dept Clin Sci, Lund, Sweden;Lund Univ, Dept Pediat, Lund, Sweden;Skane Univ Hosp, Lund, Sweden.
    Hellström-Westas, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ingemansson, Fredrik
    Ryhov Cty Hosp, Jonkoping Cty Council, Dept Pediat, Jonkoping, Sweden.
    Källén, Karin
    Lund Univ, Ctr Reprod Epidemiol, Lund, Sweden.
    Ley, David
    Lund Univ, Dept Clin Sci, Lund, Sweden;Lund Univ, Dept Pediat, Lund, Sweden;Skane Univ Hosp, Lund, Sweden.
    Marsal, Karel
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Lund, Sweden;Lund Univ, Skane Univ Hosp, Dept Obstet & Gynecol, Lund, Sweden.
    Normann, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Serenius, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stephansson, Olof
    Karolinska Inst, Div Clin Epidemiol, Dept Med, Stockholm, Sweden;Karolinska Inst, Div Obstet & Gynecol, Dept Womens & Childrens Hlth, Stockholm, Sweden.
    Stigson, Lennart
    Gothenburg Univ, Sahlgrenska Acad, Queen Silvia Childrens Hosp, Dept Pediat,Inst Clin Sci, Gothenburg, Sweden.
    Um-Bergström, Petra
    Karolinska Inst, Sodersjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden;Soder Sjukhuset, Dept Neonatal Med, Sachs Children & Youth Hosp, Stockholm, Sweden.
    Håkansson, Stellan
    Umea Univ Hosp, Umea, Sweden;Umea Univ, Dept Clin Sci, Umea, Sweden;Umea Univ, Dept Pediat, Umea, Sweden.
    Association Between Year of Birth and 1-Year Survival Among Extremely Preterm Infants in Sweden During 2004-2007 and 2014-20162019In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 321, no 12, p. 1188-1199Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Since 2004-2007, national guidelines and recommendations have been developed for the management of extremely preterm births in Sweden. If and how more uniform management has affected infant survival is unknown. OBJECTIVE To compare survival of extremely preterm infants born during 2004-2007 with survival of infants born during 2014-2016. DESIGN, SETTING AND PARTICIPANTS All births at 22-26weeks' gestational age (n = 2205) between April 1, 2004, and March 31, 2007, and between January 1, 2014, and December 31, 2016, in Sweden were studied. Prospective data collection was used during 2004-2007. Data were obtained from the Swedish pregnancy, medical birth, and neonatal quality registries during 2014-2016. EXPOSURES Delivery at 22-26 weeks' gestational age. MAIN OUTCOMES AND MEASURES The primary outcomewas infant survival to the age of 1 year. The secondary outcome was 1-year survival among live-born infants who did not have any major neonatal morbidity (specifically, without intraventricular hemorrhage grade 3-4, cystic periventricular leukomalacia, necrotizing enterocolitis, retinopathy of prematurity stage 3-5, or severe bronchopulmonary dysplasia). RESULTS During 2004-2007, 1009 births (3.3/1000 of all births) occurred at 22-26 weeks' gestational age compared with 1196 births (3.4/1000 of all births) during 2014-2016 (P =.61). One-year survival among live-born infants at 22-26 weeks' gestational age was significantly lower during 2004-2007 (497 of 705 infants [70%]) than during 2014-2016 (711 of 923 infants [77%]) (difference, -7%[95% CI, -11% to -2.2%], P =.003). One-year survival among live-born infants at 22-26 weeks' gestational age and without any major neonatal morbidity was significantly lower during 2004-2007 (226 of 705 infants [32%]) than during 2014-2016 (355 of 923 infants [38%]) (difference, -6%[95% CI, -11% to -1.7%], P =.008). CONCLUSIONS AND RELEVANCE Among live births at 22-26 weeks' gestational age in Sweden, 1-year survival improved between 2004-2007 and 2014-2016.

  • 39. O'Donoghue, Michelle
    et al.
    Boden, William E.
    Braunwald, Eugene
    Cannon, Christopher P.
    Clayton, Tim C.
    de Winter, Robbert J.
    Fox, Keith A. A.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    McCullough, Peter A.
    Murphy, Sabina A.
    Spacek, Rudolf
    Swahn, Eva
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Windhausen, Fons
    Sabatine, Marc S.
    Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction: a meta-analysis2008In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 300, no 1, p. 71-80Article, review/survey (Refereed)
    Abstract [en]

    CONTEXT: Although an invasive strategy is frequently used in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), data from some trials suggest that this strategy may not benefit women. OBJECTIVE: To conduct a meta-analysis of randomized trials to compare the effects of an invasive vs conservative strategy in women and men with NSTE ACS. DATA SOURCES: Trials were identified through a computerized literature search of the MEDLINE and Cochrane databases (1970-April 2008) using the search terms invasive strategy, conservative strategy, selective invasive strategy, acute coronary syndromes, non-ST-elevation myocardial infarction, and unstable angina. STUDY SELECTION: Randomized clinical trials comparing an invasive vs conservative treatment strategy in patients with NSTE ACS. DATA EXTRACTION: The principal investigators for each trial provided the sex-specific incidences of death, myocardial infarction (MI), and rehospitalization with ACS through 12 months of follow-up. DATA SYNTHESIS: Data were combined across 8 trials (3075 women and 7075 men). The odds ratio (OR) for the composite of death, MI, or ACS for invasive vs conservative strategy in women was 0.81 (95% confidence interval [CI], 0.65-1.01; 21.1% vs 25.0%) and in men was 0.73 (95% CI, 0.55-0.98; 21.2% vs 26.3%) without significant heterogeneity between sexes (P for interaction = .26). Among biomarker-positive women, an invasive strategy was associated with a 33% lower odds of death, MI, or ACS (OR, 0.67; 95% CI, 0.50-0.88) and a nonsignificant 23% lower odds of death or MI (OR, 0.77; 95% CI, 0.47-1.25). In contrast, an invasive strategy was not associated with a significant reduction in the triple composite end point in biomarker-negative women (OR, 0.94; 95% CI, 0.61-1.44; P for interaction = .36) and was associated with a nonsignificant 35% higher odds of death or MI (OR, 1.35; 95% CI, 0.78-2.35; P for interaction = .08). Among men, the OR for death, MI, or ACS was 0.56 (95% CI, 0.46-0.67) if biomarker-positive and 0.72 (95% CI, 0.51-1.01) if biomarker-negative (P for interaction = .09). CONCLUSIONS: In NSTE ACS, an invasive strategy has a comparable benefit in men and high-risk women for reducing the composite end point of death, MI, or rehospitalization with ACS. In contrast, our data provide evidence supporting the new guideline recommendation for a conservative strategy in low-risk women.

  • 40.
    Persson, Lars-Åke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Arifeen, Shams
    Ekström, Eva-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Prenatal Micronutrient and Early Pregnancy Food Supplementation in Bangladesh Reply2012In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 308, no 10, p. 971-972Article in journal (Refereed)
  • 41.
    Persson, Lars-Åke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Arifeen, Shams
    Ekström, Eva-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Rasmussen, Kathleen M.
    Frongillo, Edward A.
    Yunus, Md
    Effects of Prenatal Micronutrient and Early Food Supplementation on Maternal Hemoglobin, Birth Weight, and Infant Mortality Among Children in Bangladesh: The MINIMat Randomized Trial2012In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 307, no 19, p. 2050-2059Article in journal (Refereed)
    Abstract [en]

    Context: Nutritional insult in fetal life and small size at birth are common in low-income countries and are associated with serious health consequences.

    Objectives: To test the hypothesis that prenatal multiple micronutrient supplementation (MMS) and an early invitation to food supplementation would increase maternal hemoglobin level and birth weight and decrease infant mortality, and to assess whether a combination of these interventions would further enhance these outcomes.

    Design, Setting, and Participants: A randomized trial with a factorial design in Matlab, Bangladesh, of 4436 pregnant women, recruited between November 11, 2001, and October 30, 2003, with follow-up until June 23, 2009.

    Interventions: Participants were randomized into 6 groups; a double-masked supplementation with capsules of 30 mg of iron and 400 mu g of folic acid, 60 mg of iron and 400 mu g of folic acid, or MMS containing a daily allowance of 15 micronutrients, including 30 mg of iron and 400 mu g of folic acid, was combined with food supplementation (608 kcal 6 days per week) randomized to either early invitation (9 weeks' gestation) or usual invitation (20 weeks' gestation).

    Main Outcome Measures: Maternal hemoglobin level at 30 weeks' gestation, birth weight, and infant mortality. Under 5-year mortality was also assessed.

    Results: Adjusted maternal hemoglobin level at 30 weeks' gestation was 115.0 g/L(95% CI, 114.4-115.5 g/L), with no significant differences among micronutrient groups. Mean maternal hemoglobin level was lower in the early vs usual invitation groups (114.5 vs 115.4 g/L; difference, -0.9 g/L; 95% CI, -1.7 to -0.1; P=.04). There were 3625 live births out of 4436 pregnancies. Mean birth weight among 3267 singletons was 2694 g(95% CI, 2680-2708 g), with no significant differences among groups. The early invitation with MMS group had an infant mortality rate of 16.8 per 1000 live births vs 44.1 per 1000 live births for usual invitation with 60 mg of iron and 400 mu g of folic acid (hazard ratio [HR], 0.38; 95% CI, 0.18-0.78). Early invitation with MMS group had an under 5-year mortality rate of 18 per 1000 live births (54 per 1000 live births for usual invitation with 60 mg of iron and 400 mu g of folic acid; HR, 0.34; 95% CI, 0.18-0.65). Usual invitation with MMS group had the highest incidence of spontaneous abortions and the highest infant mortality rate.

    Conclusion: Among pregnant women in poor communities in Bangladesh, treatment with multiple micronutrients, including iron and folic acid combined with early food supplementation, vs a standard program that included treatment with iron and folic acid and usual food supplementation, resulted in decreased childhood mortality.

  • 42.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cardiopulmonary Resuscitation With Mechanical Chest Compressions and Simultaneous Defibrillation Reply2014In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 311, no 21, p. 2234-2235Article in journal (Refereed)
  • 43.
    Rubertsson, Sten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lindgren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Smekal, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Östlund, Ollie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Silfverstolpe, Johan
    Lichtveld, Robert A.
    Boomars, Rene
    Ahlstedt, Bjorn
    Skoog, Gunnar
    Kastberg, Robert
    Halliwell, David
    Box, Martyn
    Herlitz, Johan
    Karlsten, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Mechanical Chest Compressions and Simultaneous Defibrillation vs Conventional Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest The LINC Randomized Trial2014In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 311, no 1, p. 53-61Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE A strategy using mechanical chest compressions might improve the poor outcome in out-of-hospital cardiac arrest, but such a strategy has not been tested in large clinical trials. OBJECTIVE To determine whether administering mechanical chest compressions with defibrillation during ongoing compressions (mechanical CPR), compared with manual cardiopulmonary resuscitation (manual CPR), according to guidelines, would improve 4-hour survival. DESIGN, SETTING, AND PARTICIPANTS Multicenter randomized clinical trial of 2589 patients with out-of-hospital cardiac arrest conducted between January 2008 and February 2013 in 4 Swedish, 1 British, and 1 Dutch ambulance services and their referring hospitals. Duration of follow-up was 6 months. INTERVENTIONS Patients were randomized to receive either mechanical chest compressions (LUCAS Chest Compression System, Physio-Control/Jolife AB) combined with defibrillation during ongoing compressions (n = 1300) or to manual CPR according to guidelines (n = 1289). MAIN OUTCOMES AND MEASURES Four-hour survival, with secondary end points of survival up to 6 months with good neurological outcome using the Cerebral Performance Category (CPC) score. A CPC score of 1 or 2 was classified as a good outcome. RESULTS Four-hour survival was achieved in 307 patients (23.6%) with mechanical CPR and 305 (23.7%) with manual CPR (risk difference, -0.05%; 95% CI, -3.3% to 3.2%; P > .99). Survival with a CPC score of 1 or 2 occurred in 98 (7.5%) vs 82 (6.4%) (risk difference, 1.18%; 95% CI, -0.78% to 3.1%) at intensive care unit discharge, in 108 (8.3%) vs 100 (7.8%) (risk difference, 0.55%; 95% CI, -1.5% to 2.6%) at hospital discharge, in 105 (8.1%) vs 94 (7.3%) (risk difference, 0.78%; 95% CI, -1.3% to 2.8%) at 1 month, and in 110 (8.5%) vs 98 (7.6%) (risk difference, 0.86%; 95% CI, -1.2% to 3.0%) at 6 months with mechanical CPR and manual CPR, respectively. Among patients surviving at 6 months, 99% in the mechanical CPR group and 94% in the manual CPR group had CPC scores of 1 or 2. CONCLUSIONS AND RELEVANCE Among adults with out-of-hospital cardiac arrest, there was no significant difference in 4-hour survival between patients treated with the mechanical CPR algorithm or those treated with guideline-adherent manual CPR. The vast majority of survivors in both groups had good neurological outcomes by 6 months. In clinical practice, mechanical CPR using the presented algorithm did not result in improved effectiveness compared with manual CPR.

  • 44.
    Sanner, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    A comparison of public attitudes toward autopsy, organ donation, and anatomic dissection: a Swedish survey1994In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 271, no 4, p. 284-288Article in journal (Refereed)
    Abstract [en]

    Objective.—To evaluate people's reactions to procedures involving the dead body by comparing their attitudes toward autopsy, organ donation, and dissection.

    Design.—Survey, using a questionnaire with 24 items that address reactions toward autopsy, organ donation, and donation of the whole body, including religious and sociodemographic issues.

    Participants.—An age-stratified, random sample of 1950 individuals in Sweden, 18 to 75 years old. The response rate was 65%.

    Results.—Eighty-four percent reported acceptance of an autopsy for themselves and 80% for a close relative. Sixty-two percent were willing to donate their own organs and 39% to donate the organs of a family member; 15% accepted donation of their whole body for dissection. Practically all who accepted dissection also were willing to donate their organs and to be autopsied; practically all who were willing to donate their organs also accepted autopsy. About 65% to 70% felt some discomfort at the thought of autopsy and organ donation. Women seemed more sensitive toward operations on the dead body than men.

    Conclusions.—The rank order of medical procedures after death, based on the proportion of individuals positive toward the procedures, can be used to form a scale with autopsy and dissection at each end point and organ donation in the middle. This scale has the characteristics of a Guttman scale and can be looked on as a comfort-discomfort continuum regarding procedures involving the dead body.

  • 45. Schultz, Johannes Kurt
    et al.
    Yaqub, Sheraz
    Wallon, Conny
    Blecic, Ljiljana
    Forsmo, Håvard Mjørud
    Folkesson, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Buchwald, Pamela
    Körner, Hartwig
    Dahl, Fredrik A
    Øresland, Tom
    chabok, abbas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Laparoscopic Lavage vs Primary Resection for Acute Perforated Diverticulitis: The SCANDIV Randomized Clinical Trial2015In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 314, no 13, p. 1364-1375Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Perforated colonic diverticulitis usually requires surgical resection, which is associated with significant morbidity. Cohort studies have suggested that laparoscopic lavage may treat perforated diverticulitis with less morbidity than resection procedures.

    OBJECTIVE: To compare the outcomes from laparoscopic lavage with those for colon resection for perforated diverticulitis.

    DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized clinical superiority trial recruiting participants from 21 centers in Sweden and Norway from February 2010 to June 2014. The last patient follow-up was in December 2014 and final review and verification of the medical records was assessed in March 2015. Patients with suspected perforated diverticulitis, a clinical indication for emergency surgery, and free air on an abdominal computed tomography scan were eligible. Of 509 patients screened, 415 were eligible and 199 were enrolled.

    INTERVENTIONS: Patients were assigned to undergo laparoscopic peritoneal lavage (n = 101) or colon resection (n = 98) based on a computer-generated, center-stratified block randomization. All patients with fecal peritonitis (15 patients in the laparoscopic peritoneal lavage group vs 13 in the colon resection group) underwent colon resection. Patients with a pathology requiring treatment beyond that necessary for perforated diverticulitis (12 in the laparoscopic lavage group vs 13 in the colon resection group) were also excluded from the protocol operations and treated as required for the pathology encountered.

    MAIN OUTCOMES AND MEASURES: The primary outcome was severe postoperative complications (Clavien-Dindo score >IIIa) within 90 days. Secondary outcomes included other postoperative complications, reoperations, length of operating time, length of postoperative hospital stay, and quality of life.

    RESULTS: The primary outcome was observed in 31 of 101 patients (30.7%) in the laparoscopic lavage group and 25 of 96 patients (26.0%) in the colon resection group (difference, 4.7% [95% CI, -7.9% to 17.0%]; P = .53). Mortality at 90 days did not significantly differ between the laparoscopic lavage group (14 patients [13.9%]) and the colon resection group (11 patients [11.5%]; difference, 2.4% [95% CI, -7.2% to 11.9%]; P = .67). The reoperation rate was significantly higher in the laparoscopic lavage group (15 of 74 patients [20.3%]) than in the colon resection group (4 of 70 patients [5.7%]; difference, 14.6% [95% CI, 3.5% to 25.6%]; P = .01) for patients who did not have fecal peritonitis. The length of operating time was significantly shorter in the laparoscopic lavage group; whereas, length of postoperative hospital stay and quality of life did not differ significantly between groups. Four sigmoid carcinomas were missed with laparoscopic lavage.

    CONCLUSIONS AND RELEVANCE: Among patients with likely perforated diverticulitis and undergoing emergency surgery, the use of laparoscopic lavage vs primary resection did not reduce severe postoperative complications and led to worse outcomes in secondary end points. These findings do not support laparoscopic lavage for treatment of perforated diverticulitis.

    TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01047462.

  • 46. Schwan, Sofie
    et al.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Escitalopram treatment of generalized anxiety disorder in older adults2009In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 301, no 19, p. 1987-1988; author reply 1988Article in journal (Refereed)
  • 47.
    Sennerby, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gedeborg, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Garmo, Hans
    Regional Oncologic Center, Uppsala University, Uppsala .
    Ahlbom, Anders
    Pedersen, Nancy L.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Cardiovascular diseases and risk of hip fracture2009In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 302, no 15, p. 1666-1673Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Recent studies indicate common etiologies for cardiovascular disease (CVD) and osteoporotic fractures. OBJECTIVES: To examine the relation between CVD and risk of hip fracture in twins and evaluate the relative importance of genetics and lifestyle factors in this association. DESIGN, SETTING, AND PARTICIPANTS: A cohort of all 31,936 Swedish twins born from 1914-1944 was followed up from the age of 50 years. The National Patient Registry identified twins with CVDs and fractures from 1964 through 2005. Time-dependent exposures using Cox proportional hazard regression models were evaluated. MAIN OUTCOME MEASURE: Time to hip fracture after diagnosis of CVD. RESULTS: The crude absolute rate of hip fractures was 12.6 per 1000 person-years after a diagnosis of heart failure, 12.6 per 1000 person-years after a stroke, 6.6 per 1000 person-years after a diagnosis of peripheral atherosclerosis, and 5.2 per 1000 person-years after a diagnosis of ischemic heart disease compared with 1.2 per 1000 person-years for those without a CVD diagnosis. The multivariable-adjusted hazard ratio (HR) of hip fracture after a diagnosis of heart failure was 4.40 (95% confidence interval [CI], 3.43-5.63); after a stroke, the HR was 5.09 (95% CI, 4.18-6.20); after a diagnosis of peripheral atherosclerosis, the HR was 3.20 (95% CI, 2.28-4.50); and after an ischemic heart disease event, the HR was 2.32 (95% CI, 1.91-2.84). Identical twins without heart failure and stroke also had, after their co-twins had been exposed to these respective diseases, an increased rate of hip fracture. These sibling twins pseudoexposed for heart failure had a multivariable-adjusted HR of 3.74 (95% CI, 1.97-7.10) for hip fracture, whereas pseudoexposure for stroke had an HR of 2.29 (95% CI, 1.20-4.35). CONCLUSIONS: A diagnosis of CVD was significantly associated with risk of subsequent hip fracture. Increased risks in co-twins without an index diagnosis suggest genetic factors in the association between CVD and osteoporotic fractures.

  • 48.
    Serenius, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Källén, Karin
    Centre of Reproductive Epidemiology, Lund University, Sweden.
    Blennow, Mats
    Departments of Clinical Science, Intervention, and Technology, Karolinska Institutet, Sweden.
    Ewald, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Fellman, Vineta
    Departments of Pediatrics, Clinical Sciences Lund, Lund University, Sweden.
    Holmström, Gerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Lindberg, Eva
    Department of Pediatrics, Örebro University, Sweden.
    Lundqvist, Pia
    Departments of Pediatrics, Health Sciences, Lund University, Sweden.
    Maršál, Karel
    Departments of Obstetrics and Gynecology, Clinical Sciences Lund, Lund University, Sweden.
    Norman, Mikael
    Departments of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
    Olhager, Elisabeth
    Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Stigson, Lennart
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Sweden.
    Stjernqvist, Karin
    Psychology, Lund University, Sweden.
    Vollmer, Brigitte
    Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Strömberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Neurodevelopmental outcome in extremely preterm infants at 2.5 years after active perinatal care in Sweden2013In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 309, no 17, p. 1810-1820Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Active perinatal care increases survival of extremely preterm infants; however, improved survival might be associated with increased disability among survivors.

    OBJECTIVE: To determine neurodevelopmental outcome in extremely preterm children at 2.5 years (corrected age).

    DESIGN, SETTING, AND PARTICIPANTS: Population-based prospective cohort of consecutive extremely preterm infants born before 27 weeks of gestation in Sweden between 2004 and 2007. Of 707 live-born infants, 491 (69%) survived to 2.5 years. Survivors were assessed and compared with singleton control infants who were born at term and matched by sex, ethnicity, and municipality. Assessments ended in February 2010 and comparison estimates were adjusted for demographic differences. MAIN OUTCOMES AND MEASURES: Cognitive, language, and motor development was assessed with Bayley Scales of Infant and Toddler Development (3rd edition; Bayley-lll), which are standardized to mean (SD) scores of 100 (15). Clinical examination and parental questionnaires were used for diagnosis of cerebral palsy and visual and hearing impairments. Assessments were made by week of gestational age.

    RESULTS: At a median age of 30.5 months (corrected), 456 of 491 (94%) extremely preterm children were evaluated (41 by chart review only). For controls, 701 had information on health status and 366 had Bayley-lll assessments. Mean (SD) composite Bayley-III scores (cognition, 94 [12.3]; language, 98 [16.5]; motor, 94 [15.9]) were lower than the corresponding mean scores for controls (cognition, 104 [10.6]; P < .001; adjusted difference in mean scores, 9.2 [99% CI, 6.9-11.5]; language, 109 [12.3]; P < .001; adjusted difference in mean scores, 9.3 [99% Cl, 6.4-12.3]; and motor, 107 [13.7]; P < .001; adjusted difference in mean scores, 12.6 [99% Cl, 9.5-15.6]). Cognitive disability was moderate in 5% of the extremely preterm group vs 0.3% in controls (P < .001) and it was severe in 6.3% of the extremely preterm group vs 0.3% in controls (P < .001). Language disability was moderate in 9.4% of the extremely preterm group vs 2.5% in controls (P < .001) and severe in 6.6% of the extremely preterm group vs 0% in controls (P < .001). Other comparisons between the extremely preterm group vs controls were for cerebral palsy (7.0% vs 0.1%; P < .001), for blindness (0.9% vs 0%; P = .02), and for hearing impairment (moderate and severe, 0.9% vs 0%; P = .02, respectively). Overall, 42% (99% CI, 36%-48%) of extremely preterm children had no disability, 31% (99% CI, 25%-36%) had mild disability, 16% (99% CI, 12%-21%) had moderate disability, and 11% (99% CI, 7.2%-15%) had severe disability. Moderate or severe overall disability decreased with gestational age at birth (22 weeks, 60%; 23 weeks, 51%; 24 weeks, 34%; 25 weeks, 27%; and 26 weeks, 17%; P for trend < .001).

    CONCLUSIONS AND RELEVANCE: Of children born extremely preterm and receiving active perinatal care, 73% had mild or no disability and neurodevelopmental outcome improved with each week of gestational age. These results are relevant for clinicians counseling families facing extremely preterm birth.

  • 49. Smith-Warner, Stephanie A.
    et al.
    Spiegelman, Donna
    Yuan, Shiaw-Shyuan
    van den Brandt, Piet A.
    Folsom, Aaron R.
    Goldbohm, R. Alexandra
    Graham, Saxon
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Howe, Geoffrey R.
    Marshall, James R.
    Miller, Anthony B.
    Potter, John D.
    Speizer, Frank E.
    Willett, Walter
    Wolk, Alicja
    Hunter, David J.
    Alcohol and breast cancer in women: A pooled analysis of cohort studies1998In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 279, no 7, p. 535-540Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess the risk of invasive breast cancer associated with total and beverage-specific alcohol consumption and to evaluate whether dietary and nondietary factors modify the association. DATA SOURCES: We included in these analyses 6 prospective studies that had at least 200 incident breast cancer cases, assessed long-term intake of food and nutrients, and used a validated diet assessment instrument. The studies were conducted in Canada, the Netherlands, Sweden, and the United States. Alcohol intake was estimated by food frequency questionnaires in each study. The studies included a total of 322647 women evaluated for up to 11 years, including 4335 participants with a diagnosis of incident invasive breast cancer. DATA EXTRACTION: Pooled analysis of primary data using analyses consistent with each study's original design and the random-effects model for the overall pooled analyses. DATA SYNTHESIS: For alcohol intakes less than 60 g/d (reported by >99% of participants), risk increased linearly with increasing intake; the pooled multivariate relative risk for an increment of 10 g/d of alcohol (about 0.75-1 drink) was 1.09 (95% confidence interval [CI], 1.04-1.13; P for heterogeneity among studies, .71). The multivariate-adjusted relative risk for total alcohol intakes of 30 to less than 60 g/d (about 2-5 drinks) vs nondrinkers was 1.41 (95% CI, 1.18-1.69). Limited data suggested that alcohol intakes of at least 60 g/d were not associated with further increased risk. The specific type of alcoholic beverage did not strongly influence risk estimates. The association between alcohol intake and breast cancer was not modified by other factors. CONCLUSIONS: Alcohol consumption is associated with a linear increase in breast cancer incidence in women over the range of consumption reported by most women. Among women who consume alcohol regularly, reducing alcohol consumption is a potential means to reduce breast cancer risk.

  • 50. Song, Huan
    et al.
    Fang, Fang
    Tomasson, Gunnar
    Arnberg, Filip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, National Center for Disaster Psychiatry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Mataix-Cols, David
    Fernández de la Cruz, Lorena
    Almqvist, Catarina
    Fall, Katja
    Valdimarsdóttir, Unnur A
    Association of Stress-Related Disorders With Subsequent Autoimmune Disease2018In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 319, no 23, p. 2388-2400Article in journal (Refereed)
    Abstract [en]

    Importance: Psychiatric reactions to life stressors are common in the general population and may result in immune dysfunction. Whether such reactions contribute to the risk of autoimmune disease remains unclear.

    Objective: To determine whether there is an association between stress-related disorders and subsequent autoimmune disease.

    Design, Setting, and Participants: Population- and sibling-matched retrospective cohort study conducted in Sweden from January 1, 1981, to December 31, 2013. The cohort included 106 464 exposed patients with stress-related disorders, with 1 064 640 matched unexposed persons and 126 652 full siblings of these patients.

    Exposures: Diagnosis of stress-related disorders, ie, posttraumatic stress disorder, acute stress reaction, adjustment disorder, and other stress reactions.

    Main Outcomes and Measures: Stress-related disorder and autoimmune diseases were identified through the National Patient Register. The Cox model was used to estimate hazard ratios (HRs) with 95% CIs of 41 autoimmune diseases beyond 1 year after the diagnosis of stress-related disorders, controlling for multiple risk factors.

    Results: The median age at diagnosis of stress-related disorders was 41 years (interquartile range, 33-50 years) and 40% of the exposed patients were male. During a mean follow-up of 10 years, the incidence rate of autoimmune diseases was 9.1, 6.0, and 6.5 per 1000 person-years among the exposed, matched unexposed, and sibling cohorts, respectively (absolute rate difference, 3.12 [95% CI, 2.99-3.25] and 2.49 [95% CI, 2.23-2.76] per 1000 person-years compared with the population- and sibling-based reference groups, respectively). Compared with the unexposed population, patients with stress-related disorders were at increased risk of autoimmune disease (HR, 1.36 [95% CI, 1.33-1.40]). The HRs for patients with posttraumatic stress disorder were 1.46 (95% CI, 1.32-1.61) for any and 2.29 (95% CI, 1.72-3.04) for multiple (≥3) autoimmune diseases. These associations were consistent in the sibling-based comparison. Relative risk elevations were more pronounced among younger patients (HR, 1.48 [95% CI, 1.42-1.55]; 1.41 [95% CI, 1.33-1.48]; 1.31 [95% CI, 1.24-1.37]; and 1.23 [95% CI, 1.17-1.30] for age at ≤33, 34-41, 42-50, and ≥51 years, respectively; P for interaction < .001). Persistent use of selective serotonin reuptake inhibitors during the first year of posttraumatic stress disorder diagnosis was associated with attenuated relative risk of autoimmune disease (HR, 3.64 [95% CI, 2.00-6.62]; 2.65 [95% CI, 1.57-4.45]; and 1.82 [95% CI, 1.09-3.02] for duration ≤179, 180-319, and ≥320 days, respectively; P for trend = .03).

    Conclusions and Relevance: In this Swedish cohort, exposure to a stress-related disorder was significantly associated with increased risk of subsequent autoimmune disease, compared with matched unexposed individuals and with full siblings. Further studies are needed to better understand the underlying mechanisms.

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