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  • 1.
    Alirol, Emilie
    et al.
    Global Antibiotics Research and Development Partnership (GARDP), Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
    Wi, Teodora E.
    World Health Organization (WHO), Geneva, Switzerland.
    Bala, Manju
    Regional STD Teaching, Training & Research Centre, VMMC and Safdarjung Hospital, New Delhi, India.
    Bazzo, Maria Luiza
    Federal University of Santa Catarina, Florianópolis, Brazil.
    Chen, Xiang-Sheng
    National Center for STD Control, Chinese Academy of Medical Sciences, Nanjing, China; Peking Union Medical College Institute of Dermatology, Nanjing, China.
    Deal, Carolyn
    STD Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), Rockville MD, United States of America.
    Dillon, Jo-Anne R.
    University of Saskatchewan, Saskatoon SK, Canada.
    Kularatne, Ranmini
    Centre for HIV & Sexually Transmitted Infections, National Institute for Communicable Diseases, Johannesburg, South Africa.
    Heim, Jutta
    Global Antibiotics Research and Development Partnership (GARDP), Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
    Hooft van Huijsduijnen, Rob
    Global Antibiotics Research and Development Partnership (GARDP), Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
    Hook, Edward W.
    University of Alabama, Birmingham AL, United States of America.
    Lahra, Monica M.
    World Health Organization Collaborating Centre for Sexually Transmitted Diseases, South Eastern Area Laboratory Services, The Prince of Wales Hospital, Sydney, Australia.
    Lewis, David A.
    Western Sydney Sexual Health Centre, Parramatta NSW, Australia; Marie Bashir Institute for Infectious Diseases and Biosecurity, Sydney Medical School-Westmead, University of Sydney, Westmead, Australia.
    Ndowa, Francis
    Skin & GU Medicine Clinic, Harare, Zimbabwe.
    Shafer, William M.
    Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta GA, United States of America; Laboratories of Bacterial Pathogenesis, VA Medical Center, Decatur GA, United States of America.
    Tayler, Liz
    World Health Organization (WHO), Geneva, Switzerland.
    Workowski, Kimberly
    Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta GA, United States of America.
    Unemo, Magnus
    World Health Organization Collaborating Centre for Gonorrhoea and other STIs, Örebro University Hospital, Örebro, Sweden.
    Balasegaram, Manica
    Global Antibiotics Research and Development Partnership (GARDP), Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
    Multidrug-resistant gonorrhea: A research and development roadmap to discover new medicines2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 7, article id e1002366Article in journal (Refereed)
    Abstract [en]

    Emilie Alirol and colleagues discuss the development of new treatments for gonorrhea.

  • 2.
    Al-Jebari, Yahia
    et al.
    Lund Univ, Mol Reprod Med, Dept Translat Med, Malmo, Sweden.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Div Clin Epidemiol, Dept Med, Stockholm, Sweden.
    Nord, Carina Berglund
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Cohn-Cedermark, Gabriella
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Stahl, Olof
    Skane Univ Hosp, Dept Oncol, Lund, Sweden.
    Tandstad, Torgrim
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Fac Med & Hlth Sci, Trondheim, Norway;St Olavs Univ Hosp, Canc Clin, Trondheim, Norway.
    Jensen, Allan
    Danish Canc Soc Res Ctr, Virus Lifestyle & Genes, Copenhagen, Denmark.
    Haugnes, Hege Sagstuen
    Univ Hosp North Norway, Dept Oncol, Tromso, Norway;UiT Arctic Univ Norway, Inst Clin Med, Tromso, Norway.
    Daugaard, Gedske
    Rigshosp, Dept Oncol, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Rylander, Lars
    Lund Univ, Div Occupat & Environm Med, Lund, Sweden.
    Giwercman, Aleksander
    Lund Univ, Mol Reprod Med, Dept Translat Med, Malmo, Sweden.
    Cancer therapy and risk of congenital malformations in children fathered by men treated for testicular germ-cell cancer: A nationwide register study2019In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, no 6, article id e1002816Article in journal (Refereed)
    Abstract [en]

    Background Because of the potential mutagenic effects of chemo- and radiotherapy, there is concern regarding increased risk of congenital malformations (CMs) among children of fathers with cancer. Previous register studies indicate increased CM risk among children conceived after paternal cancer but lack data on oncological treatment. Increased CM risk was recently reported in children born before paternal cancer. This study aims to investigate whether anti-neoplastic treatment for testicular germ-cell cancer (TGCC) implies additional CM risk. Methods and findings In this nationwide register study, all singletons born in Sweden 1994-2014 (n = 2,027,997) were included. Paternal TGCC diagnoses (n = 2,380), anti-neoplastic treatment, and offspring CMs were gathered from the Swedish Norwegian Testicular Cancer Group (SWENOTECA) and the Swedish Medical Birth Register. Children were grouped based on +/- paternal TGCC; treatment regimen: surveillance (n = 1,340), chemotherapy (n = 2,533), or radiotherapy (n = 360); and according to time of conception: pre- (n = 2,770) or post-treatment (n = 1,437). Odds ratios (ORs) for CMs were calculated using logistic regression with adjustment for parental ages, maternal body mass index (BMI), and maternal smoking. Children conceived before a specific treatment acted as reference for children conceived after the same treatment. Among children fathered by men with TGCC (n = 4,207), 184 had a CM. The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19-1.38, p = 0.001, 4.4% versus 3.5%). However, no additional risk increase was associated with oncological treatment when comparing post-treatment-to pretreatment-conceived children (chemotherapy, OR = 0.82, 95% CI 0.54-1.25, p = 0.37, 4.1% versus 4.6%; radiotherapy, OR = 1.01, 95% CI 0.25-4.12, p = 0.98, 3.2% versus 3.0%). Study limitations include lack of data on use of cryopreserved or donor sperm and on seminoma patients for the period 1995-2000-both tending to decrease the difference between the groups with TGCC and without TGCC. Furthermore, the power of analyses on chemotherapy intensity and radiotherapy was limited. Conclusions No additional increased risk of CMs was observed in children of men with TGCC treated with radio- or chemotherapy. However, paternal TGCC per se was associated with modestly increased risk for offspring malformations. Clinically, this information can reassure concerned patients.

  • 3. Bengtsson, Linus
    et al.
    Lu, Xin
    Stockholm University, Faculty of Social Sciences, Department of Sociology.
    Thorson, Anna
    Garfield, Richard
    von Schreeb, Johan
    Improved Response to Disasters and Outbreaks by Tracking Population Movements with Mobile Phone Network Data: A Post-Earthquake Geospatial Study in Haiti2011In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 8, no 8, p. e1001083-Article in journal (Refereed)
    Abstract [en]

    Background: Population movements following disasters can cause important increases in morbidity and mortality. Without knowledge of the locations of affected people, relief assistance is compromised. No rapid and accurate method exists to track population movements after disasters. We used position data of subscriber identity module (SIM) cards from the largest mobile phone company in Haiti (Digicel) to estimate the magnitude and trends of population movements following the Haiti 2010 earthquake and cholera outbreak. Methods and Findings: Geographic positions of SIM cards were determined by the location of the mobile phone tower through which each SIM card connects when calling. We followed daily positions of SIM cards 42 days before the earthquake and 158 days after. To exclude inactivated SIM cards, we included only the 1.9 million SIM cards that made at least one call both pre-earthquake and during the last month of study. In Port-au-Prince there were 3.2 persons per included SIM card. We used this ratio to extrapolate from the number of moving SIM cards to the number of moving persons. Cholera outbreak analyses covered 8 days and tracked 138,560 SIM cards. An estimated 630,000 persons (197,484 Digicel SIM cards), present in Port-au-Prince on the day of the earthquake, had left 19 days post-earthquake. Estimated net outflow of people (outflow minus inflow) corresponded to 20% of the Port-au-Prince pre-earthquake population. Geographic distribution of population movements from Port-au-Prince corresponded well with results from a large retrospective, population-based UN survey. To demonstrate feasibility of rapid estimates and to identify areas at potentially increased risk of outbreaks, we produced reports on SIM card movements from a cholera outbreak area at its immediate onset and within 12 hours of receiving data. Conclusions: Results suggest that estimates of population movements during disasters and outbreaks can be delivered rapidly and with potentially high validity in areas with high mobile phone use.

  • 4. Bhattarai, Achuyt
    et al.
    Ali, Abdullah S.
    Kachur, S. Patrick
    Mårtensson, Andreas
    Abbas, Ali K.
    Khatib, Rashid
    Al-Mafazy, Abdul-Wahiyd
    Ramsan, Mahdi
    Rotllant, Guida
    Gerstenmaier, Jan F.
    Molteni, Fabrizio
    Abdulla, Salim
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Kaneko, Akira
    Björkman, Anders
    Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Zanzibar2007In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 4, no 11, p. e309-Article in journal (Refereed)
    Abstract [en]

    Background

    The Roll Back Malaria strategy recommends a combination of interventions for malaria control. Zanzibar implemented artemisinin-based combination therapy (ACT) for uncomplicated malaria in late 2003 and long-lasting insecticidal nets (LLINs) from early 2006. ACT is provided free of charge to all malaria patients, while LLINs are distributed free to children under age 5 y (“under five”) and pregnant women. We investigated temporal trends in Plasmodium falciparum prevalence and malaria-related health parameters following the implementation of these two malaria control interventions in Zanzibar.

    Methods and Findings

    Cross-sectional clinical and parasitological surveys in children under the age of 14 y were conducted in North A District in May 2003, 2005, and 2006. Survey data were analyzed in a logistic regression model and adjusted for complex sampling design and potential confounders. Records from all 13 public health facilities in North A District were analyzed for malaria-related outpatient visits and admissions. Mortality and demographic data were obtained from District Commissioner's Office. P. falciparum prevalence decreased in children under five between 2003 and 2006; using 2003 as the reference year, odds ratios (ORs) and 95% confidence intervals (CIs) were, for 2005, 0.55 (0.28–1.08), and for 2006, 0.03 (0.00–0.27); p for trend < 0.001. Between 2002 and 2005 crude under-five, infant (under age 1 y), and child (aged 1–4 y) mortality decreased by 52%, 33%, and 71%, respectively. Similarly, malaria-related admissions, blood transfusions, and malaria-attributed mortality decreased significantly by 77%, 67% and 75%, respectively, between 2002 and 2005 in children under five. Climatic conditions favorable for malaria transmission persisted throughout the observational period.

    Conclusions

    Following deployment of ACT in Zanzibar 2003, malaria-associated morbidity and mortality decreased dramatically within two years. Additional distribution of LLINs in early 2006 resulted in a 10-fold reduction of malaria parasite prevalence. The results indicate that the Millennium Development Goals of reducing mortality in children under five and alleviating the burden of malaria are achievable in tropical Africa with high coverage of combined malaria control interventions.

  • 5.
    Björklund, Peyman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    A LRP5 receptor with internal deletion in hyperparathyroid tumors with implications for deregulated Wnt/β-catenin signaling2007In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 4, no 11, p. 1829-1841Article in journal (Refereed)
    Abstract [en]

    Background Hyperparathyroidism (HPT) is a common endocrine disorder with incompletely understood etiology, characterized by enlarged hyperactive parathyroid glands and increased serum concentrations of parathyroid hormone and ionized calcium. We have recently reported activation of the Wnt signaling pathway by accumulation of beta-catenin in all analyzed parathyroid tumors from patients with primary HPT (pHPT) and in hyperplastic parathyroid glands from patients with uremia secondary to HPT (sHPT). Mechanisms that may account for this activation have not been identified, except for a few cases of beta-catenin (CTNNB1) stabilizing mutation in pHPT tumors. Methods and Findings Reverse transcription PCR and Western blot analysis showed expression of an aberrantly spliced internally truncated WNT coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) in 32 out of 37 pHPT tumors (86%) and 20 out of 20 sHPT tumors (100%). Stabilizing mutation of CTNNB1 and expression of the internally truncated LRP5 receptor was mutually exclusive. Expression of the truncated LRP5 receptor was required to maintain the nonphosphorylated active beta-catenin level, transcription activity of beta-catenin, MYC expression, parathyroid cell growth in vitro, and parathyroid tumor growth in a xenograft severe combined immunodeficiency ( SCID) mouse model. WNT3 ligand and the internally truncated LRP5 receptor strongly activated transcription, and the internally truncated LRP5 receptor was insensitive to inhibition by DKK1. Conclusions The internally truncated LRP5 receptor is strongly implicated in deregulated activation of the WNT/beta-catenin signaling pathway in hyperparathyroid tumors, and presents a potential target for therapeutic intervention.

  • 6. Bugiardini, Raffaele
    et al.
    Badimon, Lina
    Collins, Peter
    Erbel, Raimund
    Fox, Kim
    Hamm, Christian
    Pinto, Fausto
    Rosengren, Annika
    Stefanadis, Christodoulos
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Van de Werf, Frans
    Angina, "normal" coronary angiography, and vascular dysfunction: risk assessment strategies2007In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 4, no 2, p. e12-Article in journal (Refereed)
    Abstract [en]

    Chest pain may be associated with coronary arteries that appear "normal". Normal is defined here as no visible disease or luminal irregularities (less than 50%) as judged visually at coronary angiography. Normal angiography in patients with chest pain is five times more common in women than in men [1]. Among patients with chest pain and normal angiography, an unknown number are suffering from cardiac pain of ischemic origin. Uncertainty is often difficult to allay, for medical attendants as well as for patients, resulting in perpetuation of symptoms, difficulties in management, and establishment of risk of subsequent coronary events [2]. In this article, we discuss how to stratify risk in patients with chest pain and a normal coronary angiogram.

  • 7.
    Byass, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Minimally Invasive Autopsy: A New Paradigm for Understanding Global Health?2016In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 13, no 11, article id e1002173Article in journal (Refereed)
    Abstract [en]

    Peter Byass reflects on the potential niche for minimally invasive autopsies in determining cause-of-death in low- and middle-income countries.

  • 8.
    Byass, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Immpact, University of Aberdeen, Aberdeen, United Kingdom.
    The imperfect world of global health estimates2010In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 7, no 11, p. e1001006-Article in journal (Refereed)
  • 9.
    Byass, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    The unequal world of health data2009In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 6, no 11, p. e1000155-Article in journal (Refereed)
  • 10.
    Byass, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Who needs cause-of-death data?2007In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 4, no 11, p. 1715-1716 (Article nr e333)Article in journal (Refereed)
  • 11.
    Byass, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    de Courten, Maximilian
    Graham, Wendy J
    Laflamme, Lucie
    McCaw-Binns, Affette
    Sankoh, Osman A
    Tollman, Stephen M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Zaba, Basia
    Reflections on the global burden of disease 2010 estimates2013In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 10, no 7, p. e1001477-Article in journal (Refereed)
  • 12.
    Byass, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Kabudula, Chodziwadziwa W.
    MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; INDEPTH Network, Accra, Ghana.
    Mee, Paul
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Global Health and Development, Faculty of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Ngobeni, Sizzy
    MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa;.
    Silaule, Bernard
    MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa;.
    Gomez-Olive, F. Xavier
    MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; INDEPTH Network, Accra, Ghana.
    Collinson, Mark A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; INDEPTH Network, Accra, Ghana.
    Tugendhaft, Aviva
    MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; PRICELESS/PEECHi, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa .
    Wagner, Ryan G.
    MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; .
    Twine, Rhian
    MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; .
    Hofman, Karen
    MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; PRICELESS/PEECHi, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Tollman, Stephen M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; INDEPTH Network, Accra, Ghana.
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC-Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; INDEPTH Network, Accra, Ghana.
    A Successful Failure: missing the MDG4 Target for Under-Five Mortality in South Africa2015In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 12, no 12, article id e1001926Article in journal (Refereed)
  • 13.
    Byass, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Fottrell, Edward
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Collinson, Mark A
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Tollman, Stephen M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Moving from data on deaths to public health policy in Agincourt, South Africa: approaches to analysing and understanding verbal autopsy findings2010In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 7, no 8, p. e1000325-Article in journal (Refereed)
    Abstract [en]

    There were no differences between physician interpretation and probabilistic modelling that might have led to substantially different public health policy conclusions at the population level. Physician interpretation was more nuanced than the model, for example in identifying cancers at particular sites, but did not capture the uncertainty associated with individual cases. Probabilistic modelling was substantially cheaper and faster, and completely internally consistent. Both approaches characterised the rise of HIV-related mortality in this population during the period observed, and reached similar findings on other major causes of mortality. For many purposes probabilistic modelling appears to be the best available means of moving from data on deaths to public health actions. Please see later in the article for the Editors' Summary.

  • 14. Carrasquilla, German D.
    et al.
    Frumento, Paolo
    Berglund, Anita
    Borgfeldt, Christer
    Bottai, Matteo
    Chiavenna, Chiara
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Engström, Gunnar
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Magnusson, Patrik K.
    Nilsson, Peter M.
    Pedersen, Nancy L.
    Wolk, Alicja
    Leander, Karin
    Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 11, article id e1002445Article in journal (Refereed)
    Abstract [en]

    Background: Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT.

    Methods and findings: Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI -0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0-5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, -4.41 years; 95% CI -7.14 to -1.68) and haemorrhagic stroke-free (first PD, -9.51 years; 95% CI -12.77 to -6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, -1.97 years; 95% CI -3.81 to -0.13), but not with a shorter stroke-free period (fifth PD, -1.21 years; 95% CI -3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out.

    Conclusions: When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0-5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk.

  • 15. Carrasquilla, Germán D
    et al.
    Frumento, Paolo
    Berglund, Anita
    Borgfeldt, Christer
    Bottai, Matteo
    Chiavenna, Chiara
    Eliasson, Mats
    Engström, Gunnar
    Hallmans, Göran
    Jansson, Jan-Håkan
    Magnusson, Patrik K
    Nilsson, Peter M
    Pedersen, Nancy L
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Leander, Karin
    Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies.2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 11, article id e1002445Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT.

    METHODS AND FINDINGS: Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI -0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0-5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, -4.41 years; 95% CI -7.14 to -1.68) and haemorrhagic stroke-free (first PD, -9.51 years; 95% CI -12.77 to -6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, -1.97 years; 95% CI -3.81 to -0.13), but not with a shorter stroke-free period (fifth PD, -1.21 years; 95% CI -3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out.

    CONCLUSIONS: When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0-5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk.

  • 16.
    Censin, J. C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nowak, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cooper, Nicholas
    Univ Cambridge, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Dept Med Genet,Cambridge Inst Med Res, Natl Inst Hlth Res,Cambridge Biomed Res Ctr, Cambridge, England..
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Todd, John A.
    Univ Cambridge, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Dept Med Genet,Cambridge Inst Med Res, Natl Inst Hlth Res,Cambridge Biomed Res Ctr, Cambridge, England.;Univ Oxford, NIHR Oxford Biomed Res Ctr, Wellcome Trust Ctr Human Genet,Nuffield Dept Med, JDRF,Wellcome Trust Diabet & Inflammat Lab, Oxford, England..
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Childhood adiposity and risk of type 1 diabetes: A Mendelian randomization study2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 8, article id e1002362Article in journal (Refereed)
    Abstract [en]

    Background The incidence of type 1 diabetes (T1D) is increasing globally. One hypothesis is that increasing childhood obesity rates may explain part of this increase, but, as T1D is rare, intervention studies are challenging to perform. The aim of this study was to assess this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal associations. Methods and findings We created a genetic instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood adiposity in children aged 2-10 years. Summary-level association results for these 23 SNPs with childhood-onset (<17 years) T1D were extracted from a meta-analysis of genome-wide association study with 5,913 T1D cases and 8,828 reference samples. Using inverse-variance weighted Mendelian randomization analysis, we found support for an effect of childhood adiposity on T1D risk (odds ratio 1.32, 95% CI 1.06-1.64 per standard deviation score in body mass index [SDS-BMI]). A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We therefore applied Egger regression and multivariable Mendelian randomization methods to control for this type of bias and found evidence in support of a role of childhood adiposity in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40-5.44). Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the score are not known. Mendelian randomization requires large sample sizes, and power was limited to provide precise estimates. This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science Genetic Association Consortium (SSGAC), as well as meta-analysis results from a T1D genome-wide association study. Conclusions This study provides genetic support for a link between childhood adiposity and T1D risk. Together with evidence from observational studies, our findings further emphasize the importance of measures to reduce the global epidemic of childhood obesity and encourage mechanistic studies.

  • 17. Clark, Samuel J.
    et al.
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Houle, Brian
    Arteche, Adriane
    Collinson, Mark A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Tollman, Stephen M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Stein, Alan
    Young Children's Probability of Dying Before and After Their Mother's Death: A Rural South African Population-Based Surveillance Study2013In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 10, no 3, p. e1001409-Article in journal (Refereed)
    Abstract [en]

    Background: There is evidence that a young child's risk of dying increases following the mother's death, but little is known about the risk when the mother becomes very ill prior to her death. We hypothesized that children would be more likely to die during the period several months before their mother's death, as well as for several months after her death. Therefore we investigated the relationship between young children's likelihood of dying and the timing of their mother's death and, in particular, the existence of a critical period of increased risk. Methods and Findings: Data from a health and socio-demographic surveillance system in rural South Africa were collected on children 0-5 y of age from 1 January 1994 to 31 December 2008. Discrete time survival analysis was used to estimate children's probability of dying before and after their mother's death, accounting for moderators. 1,244 children (3% of sample) died from 1994 to 2008. The probability of child death began to rise 6-11 mo prior to the mother's death and increased markedly during the 2 mo immediately before the month of her death (odds ratio [OR] 7.1 [95% CI 3.9-12.7]), in the month of her death (OR 12.6 [6.2-25.3]), and during the 2 mo following her death (OR 7.0 [3.2-15.6]). This increase in the probability of dying was more pronounced for children whose mothers died of AIDS or tuberculosis compared to other causes of death, but the pattern remained for causes unrelated to AIDS/tuberculosis. Infants aged 0-6 mo at the time of their mother's death were nine times more likely to die than children aged 2-5 y. The limitations of the study included the lack of knowledge about precisely when a very ill mother will die, a lack of information about child nutrition and care, and the diagnosis of AIDS deaths by verbal autopsy rather than serostatus. Conclusions: Young children in lower income settings are more likely to die not only after their mother's death but also in the months before, when she is seriously ill. Interventions are urgently needed to support families both when the mother becomes very ill and after her death.

  • 18.
    Dalberg, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Eriksson, Johan
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Birth outcome in women with previously treated breast cancer: a population-based cohort study from Sweden2006In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 3, no 9, p. 1597-1602Article in journal (Refereed)
    Abstract [en]

    Background: Data on birth outcome and offspring health after the appearance of breast cancer are limited. The aim of this study was to assess the risk of adverse birth outcomes in women previously treated for invasive breast cancer compared with the general population of mothers. Methods and Findings: Of all 2,870,932 singleton births registered in the Swedish Medical Birth Registry during 1973-2002, 331 first births following breast cancer surgery - with a mean time to pregnancy of 37 mo (range 7-163) - were identified using linkage with the Swedish Cancer Registry. Logistic regression analysis was used. The estimates were adjusted for maternal age, parity, and year of delivery. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate infant health and mortality, delivery complications, the risk of preterm birth, and the rates of instrumental delivery and cesarean section. The large majority of births from women previously treated for breast cancer had no adverse events. However, births by women exposed to breast cancer were associated with an increased risk of delivery complications (OR 1.5, 95% CI 1.2-1.9), cesarean section (OR 1.3, 95% CI 1.0-1.7), very preterm birth (<32 wk) (OR 3.2, 95% CI 1.7-6.0), and low birth weight (<1500 g) (OR 2.9, 95% CI 1.4-5.8). A tendency towards an increased risk of malformations among the infants was seen especially in the later time period (1988-2002) (OR 2.1, 95% CI 1.2-3.7). Conclusions: It is reassuring that births overall were without adverse events, but our findings indicate that pregnancies in previously treated breast cancer patients should possibly be regarded as higher risk pregnancies, with consequences for their surveillance and management.

     

  • 19. Deschasaux, Melanie
    et al.
    Huybrechts, Inge
    Murphy, Neil
    Julia, Chantal
    Hercberg, Serge
    Srour, Bernard
    Kesse-Guyot, Emmanuelle
    Latino-Martel, Paule
    Biessy, Carine
    Casagrande, Corinne
    Jenab, Mazda
    Ward, Heather
    Weiderpass, Elisabete
    Dahm, Christina C.
    Overvad, Kim
    Kyro, Cecilie
    Olsen, Anja
    Affret, Aurelie
    Boutron-Ruault, Marie-Christine
    Mahamat-Saleh, Yahya
    Kaaks, Rudolf
    Kuehn, Tilman
    Boeing, Heiner
    Schwingshackl, Lukas
    Bamia, Christina
    Peppa, Eleni
    Trichopoulou, Antonia
    Masala, Giovanna
    Krogh, Vittorio
    Panico, Salvatore
    Tumino, Rosario
    Sacerdote, Carlotta
    Buen-de-Mesquita, Bas
    Peeters, Petra H.
    Hjartåker, Anette
    Rylander, Charlotta
    Skeie, Guri
    Ramon Quiros, J.
    Jakszyn, Paula
    Salamanca-Fernandez, Elena
    Maria Huerta, Jose
    Ardanaz, Eva
    Amiano, Pilar
    Ericson, Ulrika
    Sonestedt, Emily
    Huseinovic, Ena
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Khaw, Kay-Tee
    Wareham, Nick
    Bradbury, Kathryn E.
    Perez-Cornago, Aurora
    Tsilidis, Konstantinos K.
    Ferrari, Pietro
    Riboli, Elio
    Gunter, Marc J.
    Touvier, Mathilde
    Nutritional quality of food as represented by the FSAm-NPS nutrient profiling system underlying the Nutri-Score label and cancer risk in Europe: results from the EPIC prospective cohort study2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 9, article id e1002651Article in journal (Refereed)
    Abstract [en]

    Background

    Helping consumers make healthier food choices is a key issue for the prevention of cancer and other diseases. In many countries, political authorities are considering the implementation of a simplified labelling system to reflect the nutritional quality of food products. The Nutri-Score, a five-colour nutrition label, is derived from the Nutrient Profiling System of the British Food Standards Agency (modified version) (FSAm-NPS). How the consumption of foods with high/low FSAm-NPS relates to cancer risk has been studied in national/regional cohorts but has not been characterized in diverse European populations.

    Methods and findings

    This prospective analysis included 471,495 adults from the European Prospective Investigation into Cancer and Nutrition (EPIC, 1992-2014, median follow-up: 15.3 y), among whom there were 49,794 incident cancer cases (main locations: breast, n = 12,063; prostate, n = 6,745; colon-rectum, n = 5,806). Usual food intakes were assessed with standardized country-specific diet assessment methods. The FSAm-NPS was calculated for each food/beverage using their 100-g content in energy, sugar, saturated fatty acid, sodium, fibres, proteins, and fruits/vegetables/legumes/nuts. The FSAm-NPS scores of all food items usually consumed by a participant were averaged to obtain the individual FSAm-NPS Dietary Index (DI) scores. Multi-adjusted Cox proportional hazards models were computed. A higher FSAm-NPS DI score, reflecting a lower nutritional quality of the food consumed, was associated with a higher risk of total cancer (HRQ5 versus (Q1) = 1.07; 95% CI 1.03-1.10, P-trend < 0.001). Absolute cancer rates in those with high and low (quintiles 5 and 1) FSAm-NPS DI scores were 81.4 and 69.5 cases/10,000 person-years, respectively. Higher FSAm-NPS DI scores were specifically associated with higher risks of cancers of the colon-rectum, upper aerodigestive tract and stomach, lung for men, and liver and postmenopausal breast for women (all P < 0.05). The main study limitation is that it was based on an observational cohort using self-reported dietary data obtained through a single baseline food frequency questionnaire; thus, exposure misclassification and residual confounding cannot be ruled out.

    Conclusions

    In this large multinational European cohort, the consumption of food products with a higher FSAm-NPS score (lower nutritional quality) was associated with a higher risk of cancer. This supports the relevance of the FSAm-NPS as underlying nutrient profiling system for front-of-pack nutrition labels, as well as for other public health nutritional measures.

  • 20. Faggiano, Fabrizio
    et al.
    Allara, Elias
    Giannotta, Fabrizia
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Molinar, Roberta
    Sumnall, Harry
    Wiers, Reinout
    Michie, Susan
    Collins, Linda
    Conrod, Patricia
    Europe Needs a Central, Transparent, and Evidence-Based Approval Process for Behavioural Prevention Interventions2014In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 11, no 10, p. e1001740-Article in journal (Refereed)
  • 21.
    Fall, Katja
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
    Fang, Fang
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America; Channing Laboratory, Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
    Ye, Weimin
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Andrén, Ove
    Örebro University Hospital, Örebro, Sweden.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University Hospital, Örebro, Sweden.
    Sparén, Pär
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Klein, Georg
    The Microbiology Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden.
    Stampfer, Meir
    Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America; Channing Laboratory, Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
    Adami, Hans-Olov
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
    Valdimarsdóttir, Unnur
    Centre of Public Health Sciences, University of Iceland, Reykjavík, Iceland.
    Immediate risk for cardiovascular events and suicide following a prostate cancer diagnosis: prospective cohort study2009In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 6, no 12, p. e1000197-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Stressful life events have been shown to be associated with altered risk of various health consequences. The aim of the present study was to investigate whether the emotional stress evoked by a prostate cancer diagnosis increases the immediate risks of cardiovascular events and suicide.

    METHODS AND FINDINGS: We conducted a prospective cohort study by following all men in Sweden who were 30 y or older (n = 4,305,358) for a diagnosis of prostate cancer (n = 168,584) and their subsequent occurrence of cardiovascular events and suicide between January 1, 1961 and December 31, 2004. We used Poisson regression models to calculate relative risks (RRs) and 95% confidence intervals (CIs) of cardiovascular events and suicide among men who had prostate cancer diagnosed within 1 y to men without any cancer diagnosis. The risks of cardiovascular events and suicide were elevated during the first year after prostate cancer diagnosis, particularly during the first week. Before 1987, the RR of fatal cardiovascular events was 11.2 (95% CI 10.4-12.1) during the first week and 1.9 (95% CI 1.9-2.0) during the first year after diagnosis. From 1987, the RR for cardiovascular events, nonfatal and fatal combined, was 2.8 (95% CI 2.5-3.2) during the first week and 1.3 (95% CI 1.3-1.3) during the first year after diagnosis. While the RR of cardiovascular events declined, the RR of suicide was stable over the entire study period: 8.4 (95% CI 1.9-22.7) during the first week and 2.6 (95% CI 2.1-3.0) during the first year after diagnosis. Men 54 y or younger at cancer diagnosis demonstrated the highest RRs of both cardiovascular events and suicide. A limitation of the present study is the lack of tumor stage data, which precluded possibilities of investigating the potential impact of the disease severity on the relationship between a recent diagnosis of prostate cancer and the risks of cardiovascular events and suicide. In addition, we cannot exclude residual confounding as a possible explanation.

    CONCLUSIONS: Men newly diagnosed with prostate cancer are at increased risks for cardiovascular events and suicide. Future studies with detailed disease characteristic data are warranted.

  • 22.
    Fall, Tove
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hägg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maegi, Reedik
    Ploner, Alexander
    Fischer, Krista
    Horikoshi, Momoko
    Sarin, Antti-Pekka
    Thorleifsson, Gudmar
    Ladenvall, Claes
    Kals, Mart
    Kuningas, Maris
    Draisma, Harmen H. M.
    Ried, Janina S.
    van Zuydam, Natalie R.
    Huikari, Ville
    Mangino, Massimo
    Sonestedt, Emily
    Benyamin, Beben
    Nelson, Christopher P.
    Rivera, Natalia V.
    Kristiansson, Kati
    Shen, Huei-yi
    Havulinna, Aki S.
    Dehghan, Abbas
    Donnelly, Louise A.
    Kaakinen, Marika
    Nuotio, Marja-Liisa
    Robertson, Neil
    de Bruijn, Renee F. A. G.
    Ikram, M. Arfan
    Amin, Najaf
    Balmforth, Anthony J.
    Braund, Peter S.
    Doney, Alexander S. F.
    Doering, Angela
    Elliott, Paul
    Esko, Tonu
    Franco, Oscar H.
    Gretarsdottir, Solveig
    Hartikainen, Anna-Liisa
    Heikkila, Kauko
    Herzig, Karl-Heinz
    Holm, Hilma
    Hottenga, Jouke Jan
    Hypponen, Elina
    Illig, Thomas
    Isaacs, Aaron
    Isomaa, Bo
    Karssen, Lennart C.
    Kettunen, Johannes
    Koenig, Wolfgang
    Kuulasmaa, Kari
    Laatikainen, Tiina
    Laitinen, Jaana
    Lindgren, Cecilia
    Lyssenko, Valeriya
    Laara, Esa
    Rayner, Nigel W.
    Mannisto, Satu
    Pouta, Anneli
    Rathmann, Wolfgang
    Rivadeneira, Fernando
    Ruokonen, Aimo
    Savolainen, Markku J.
    Sijbrands, Eric J. G.
    Small, Kerrin S.
    Smit, Jan H.
    Steinthorsdottir, Valgerdur
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Taanila, Anja
    Tobin, Martin D.
    Uitterlinden, Andre G.
    Willems, Sara M.
    Willemsen, Gonneke
    Witteman, Jacqueline
    Perola, Markus
    Evans, Alun
    Ferrieres, Jean
    Virtamo, Jarmo
    Kee, Frank
    Tregouet, David-Alexandre
    Arveiler, Dominique
    Amouyel, Philippe
    Ferrario, Marco M.
    Brambilla, Paolo
    Hall, Alistair S.
    Heath, AndrewC.
    Madden, Pamela A. F.
    Martin, Nicholas G.
    Montgomery, Grant W.
    Whitfield, John B.
    Jula, Antti
    Knekt, Paul
    Oostra, Ben
    van Duijn, Cornelia M.
    Penninx, Brenda W. J. H.
    Smith, George Davey
    Kaprio, Jaakko
    Samani, Nilesh J.
    Gieger, Christian
    Peters, Annette
    Wichmann, H. -Erich
    Boomsma, Dorret I.
    de Geus, Eco J. C.
    Tuomi, TiinaMaija
    Power, Chris
    Hammond, Christopher J.
    Spector, Tim D.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Orho-Melander, Marju
    Palmer, Colin Neil Alexander
    Morris, Andrew D.
    Groop, Leif
    Jarvelin, Marjo-Riitta
    Salomaa, Veikko
    Vartiainen, Erkki
    Hofman, Albert
    Ripatti, Samuli
    Metspalu, Andres
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Pedersen, Nancy L.
    McCarthy, Mark I.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Prokopenko, Inga
    The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis2013In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 10, no 6, p. e1001474-Article in journal (Refereed)
    Abstract [en]

    Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.

  • 23. Forouhi, Nita G.
    et al.
    Imamura, Fumiaki
    Sharp, Stephen J.
    Koulman, Albert
    Schulze, Matthias B.
    Zheng, Jusheng
    Ye, Zheng
    Sluijs, Ivonne
    Guevara, Marcela
    Maria Huerta, Jose
    Kroeger, Janine
    Wang, Laura Yun
    Summerhill, Keith
    Griffin, Julian L.
    Feskens, Edith J. M.
    Affret, Aurelie
    Amiano, Pilar
    Boeing, Heiner
    Dow, Courtney
    Fagherazzi, Guy
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Lund University, Malmö, Sweden.
    Gonzalez, Carlos
    Kaaks, Rudolf
    Key, Timothy J.
    Khaw, Kay Tee
    Kuehn, Tilman
    Mortensen, Lotte Maxild
    Nilsson, Peter M.
    Overvad, Kim
    Pala, Valeria
    Palli, Domenico
    Panico, Salvatore
    Ramon Quiros, J.
    Rodriguez-Barranco, Miguel
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sacerdote, Carlotta
    Scalbert, Augustin
    Slimani, Nadia
    Spijkerman, Annemieke M. W.
    Tjonneland, Anne
    Tormo, Maria-Jose
    Tumino, Rosario
    van der A, Daphne L.
    van der Schouw, Yvonne T.
    Langenberg, Claudia
    Riboli, Elio
    Wareham, Nicholas J.
    Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study2016In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 13, no 7, article id e1002094Article in journal (Refereed)
    Abstract [en]

    Background Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these associations.

    Methods and Findings Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among long-chain n-3 PUFAs, a-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88-0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid (LA) (0.80; 95% CI 0.77-0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85-0.94) were inversely related, and arachidonic acid (AA) was not significantly associated, while significant positive associations were observed with.-linolenic acid (GLA), dihomo-GLA, docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between 1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs.

    Conclusions These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely associated with T2D. The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class.

  • 24.
    Fottrell, Edward
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Osrin, David
    Sickle Cell Anaemia in a Changing World2013In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 10, no 7, p. e1001483-Article in journal (Other academic)
  • 25.
    Gunnarsdottir, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health).
    Cnattingius, Sven
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Lundgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden..
    Ekholm Selling, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Högberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics. Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Prenatal exposure to preeclampsia is associated with accelerated height gain in early childhood2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 13, no 2, article id e0192514Article in journal (Refereed)
    Abstract [en]

    Background Preeclampsia is associated with low birth weight, both because of increased risks of preterm and of small-for-gestational-age (SGA) births. Low birth weight is associated with accelerated childhood height gain and cardiovascular diseases later in life. The aim was to investigate if prenatal exposure to preeclampsia is associated with accelerated childhood height gain, also after adjustments for SGA-status and gestational age at birth. Methods In a cohort of children prenatally exposed to preeclampsia (n = 865) or unexposed (n = 22,898) we estimated height gain between birth and five years of age. The mean difference in height gain between exposed and unexposed children was calculated and adjustments were done with linear regression models. Results Children exposed to preeclampsia were on average born shorter than unexposed. Exposed children grew on average two cm more than unexposed from birth to five years of age. After adjustments for maternal characteristics including socioeconomic factors, height, body mass index (BMI) and diabetes, as well as for parents smoking habits, infant's breastfeeding and childhood obesity, the difference was 1.6 cm (95% CI 1.3-1.9 cm). Further adjustment for SGA birth only slightly attenuated this estimate, but adjustment for gestational age at birth decreased the estimate to 0.5 cm (95% CI 0.1-0.7 cm). Conclusion Prenatal exposure to preeclampsia is associated with accelerated height gain in early childhood. The association seemed independent on SGA-status, but partly related to shorter gestational age at birth.

  • 26. Guo, Yuming
    et al.
    Gasparrini, Antonio
    Li, Shanshan
    Sera, Francesco
    Vicedo-Cabrera, Ana Maria
    de Sousa Zanotti Stagliorio Coelho, Micheline
    Saldiva, Paulo Hilario Nascimento
    Lavigne, Eric
    Tawatsupa, Benjawan
    Punnasiri, Kornwipa
    Overcenco, Ala
    Correa, Patricia Matus
    Ortega, Nicolas Valdes
    Kan, Haidong
    Osorio, Samuel
    Jaakkola, Jouni J K
    Ryti, Niilo R I
    Goodman, Patrick G
    Zeka, Ariana
    Michelozzi, Paola
    Scortichini, Matteo
    Hashizume, Masahiro
    Honda, Yasushi
    Seposo, Xerxes
    Kim, Ho
    Tobias, Aurelio
    Íñiguez, Carmen
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Oudin Åström, Daniel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Guo, Yue Leon
    Chen, Bing-Yu
    Zanobetti, Antonella
    Schwartz, Joel
    Dang, Tran Ngoc
    Van, Dung Do
    Bell, Michelle L
    Armstrong, Ben
    Ebi, Kristie L
    Tong, Shilu
    Quantifying excess deaths related to heatwaves under climate change scenarios: A multicountry time series modelling study2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 7, article id e1002629Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Heatwaves are a critical public health problem. There will be an increase in the frequency and severity of heatwaves under changing climate. However, evidence about the impacts of climate change on heatwave-related mortality at a global scale is limited.

    METHODS AND FINDINGS: We collected historical daily time series of mean temperature and mortality for all causes or nonexternal causes, in periods ranging from January 1, 1984, to December 31, 2015, in 412 communities within 20 countries/regions. We estimated heatwave-mortality associations through a two-stage time series design. Current and future daily mean temperature series were projected under four scenarios of greenhouse gas emissions from 1971-2099, with five general circulation models. We projected excess mortality in relation to heatwaves in the future under each scenario of greenhouse gas emissions, with two assumptions for adaptation (no adaptation and hypothetical adaptation) and three scenarios of population change (high variant, median variant, and low variant). Results show that, if there is no adaptation, heatwave-related excess mortality is expected to increase the most in tropical and subtropical countries/regions (close to the equator), while European countries and the United States will have smaller percent increases in heatwave-related excess mortality. The higher the population variant and the greenhouse gas emissions, the higher the increase of heatwave-related excess mortality in the future. The changes in 2031-2080 compared with 1971-2020 range from approximately 2,000% in Colombia to 150% in Moldova under the highest emission scenario and high-variant population scenario, without any adaptation. If we considered hypothetical adaptation to future climate, under high-variant population scenario and all scenarios of greenhouse gas emissions, the heatwave-related excess mortality is expected to still increase across all the countries/regions except Moldova and Japan. However, the increase would be much smaller than the no adaptation scenario. The simple assumptions with respect to adaptation as follows: no adaptation and hypothetical adaptation results in some uncertainties of projections.

    CONCLUSIONS: This study provides a comprehensive characterisation of future heatwave-related excess mortality across various regions and under alternative scenarios of greenhouse gas emissions, different assumptions of adaptation, and different scenarios of population change. The projections can help decision makers in planning adaptation and mitigation strategies for climate change.

  • 27.
    Gustafsson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Crenshaw, Albert G.
    Edmundsson, David
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Toolanen, Göran
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Muscle oxygenation in Type 1 diabetic and non-diabetic patients with and without chronic compartment syndrome2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 12, no 10, article id e0186790Article in journal (Refereed)
    Abstract [en]

    Background: Type 1 diabetic patients and non-diabetic patients were referred for evaluation for chronic exertional compartment syndrome (CECS) based on clinical examination and complaints of activity-related leg pain in the region of the tibialis anterior muscle. Previous studies using near-infrared spectroscopy (NIRS) showed greater deoxygenation during exercise for CECS patients versus healthy controls; however, this comparison has not been done for diabetic CECS patients. Methods: We used NIRS to test for differences in oxygenation kinetics for Type 1 diabetic patients diagnosed with (CECS-diabetics, n = 9) versus diabetic patients without (CON-diabetics, n = 10) leg anterior chronic exertional compartment syndrome. Comparisons were also made between non-diabetic CECS patients (n = 11) and healthy controls (CON, n = 10). The experimental protocol consisted of thigh arterial cuff occlusion (AO, 1-minute duration), and treadmill running to reproduce symptoms. NIRS variables generated were resting StO(2)%, and oxygen recovery following AO. Also, during and following treadmill running the magnitude of deoxygenation and oxygen recovery, respectively, were determined. Results: There was no difference in resting StO2% between CECS-diabetics (78.2 +/- 12.6%) vs. CON-diabetics (69.1 +/- 20.8%), or between CECS (69.3 +/- 16.2) vs. CON (75.9 +/- 11.2%). However, oxygen recovery following AO was significantly slower for CECS (1.8 +/- 0.8%/sec) vs. CON (3.8 +/- 1.7%/sec) (P = 0.002); these data were not different between the diabetic groups. StO2% during exercise was lower (greater deoxygenation) for CECS-diabetics (6.3 +/- 8.6%) vs. CON-diabetics (40.4 +/- 22.0%), and for CECS (11.3 +/- 16.8%) vs. CON (34.1 +/- 21.2%) (P<0.05 for both). The rate of oxygen recovery post exercise was faster for CECS-diabetics (3.5 +/- 2.6%/sec) vs. CON-diabetics (1.4 +/- 0.8%/sec) (P = 0.04), and there was a tendency of difference for CECS (3.1 +/- 1.4%/sec) vs. CON (1.9 +/- 1.3%/sec) (P = 0.05). Conclusion: The greater deoxygenation during treadmill running for the CECS-diabetics group (vs. CON-diabetics) is in line with previous studies (and with the present study) that compared non-diabetic CECS patients with healthy controls. Our findings could suggest that NIRS may be useful as a diagnostic tool for assessing Type 1 diabetic patients suspected of CECS.

  • 28.
    Holmberg, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Vickers, Andrew
    Evaluation of Prediction Models for Decision-Making: Beyond Calibration and Discrimination2013In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 10, no 7, p. e1001491-Article in journal (Other academic)
  • 29.
    Imamura, Fumiaki
    et al.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England.
    Fretts, Amanda
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Marklund, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Korat, Andres V. Ardisson
    Harvard TH Chan Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA USA.
    Yang, Wei-Sin
    Natl Taiwan Univ, Coll Publ Hlth, Inst Epidemiol & Prevent Med, Taipei, Taiwan.
    Lankinen, Maria
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland.
    Qureshi, Waqas
    Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Bowman Gray Ctr,Sect Cardiovasc Med, Winston Salem, NC 27103 USA.
    Helmer, Catherine
    Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France.
    Chen, Tzu-An
    USDA ARS, Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX USA.
    Wong, Kerry
    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
    Bassett, Julie K.
    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
    Murphy, Rachel
    Univ British Columbia, Fac Med, Sch Populat & Publ Hlth, Ctr Excellence Canc Prevent, Vancouver, BC, Canada.
    Tintle, Nathan
    Dordt Coll, Dept Math & Stat, Sioux Ctr, IA USA.
    Yu, Chaoyu Ian
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA.
    Brouwer, Ingeborg A.
    Vrije Univ Amsterdam, Amsterdam Publ Hlth Res Inst, Fac Earth & Life Sci, Dept Hlth Sci, Amsterdam, Netherlands.
    Chien, Kuo-Liong
    Natl Taiwan Univ, Coll Publ Hlth, Inst Epidemiol & Prevent Med, Taipei, Taiwan.
    Frazier-Wood, Alexis C.
    USDA ARS, Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX USA.
    del Gobbo, Liana C.
    Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA USA.
    Djousse, Luc
    Brigham & Womens Hosp, Dept Med, Div Aging, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA USA.
    Geleijnse, Johanna M.
    Wageningen Univ, Div Human Nutr, Wageningen, Netherlands.
    Giles, Graham G.
    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia;Univ Melbourne, Ctr Epidemiol & Biostat, Parkville, Vic, Australia.
    de Goede, Janette
    Wageningen Univ, Div Human Nutr, Wageningen, Netherlands.
    Gudnason, Vilmundur
    Iceland Heart Assoc Res Inst, Kopavogur, Iceland.
    Harris, William S.
    Univ South Dakota, Sanford Sch Med, Dept Internal Med, Sioux Falls, SD USA;OmegaQuant Analyt LLC, Sioux Falls, SD USA.
    Hodge, Allison
    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia;Univ Melbourne, Ctr Epidemiol & Biostat, Parkville, Vic, Australia.
    Hu, Frank
    Harvard TH Chan Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA USA.
    Koulman, Albert
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England;Univ Cambridge, Addenbrookes Hosp, Natl Inst Hlth Res Biomed Res Ctr Core Nutr Bioma, Cambridge, England;Univ Cambridge, Addenbrookes Hosp, Natl Inst Hlth Res Biomed Res Ctr Core Metabol &, Cambridge, England;MRC, Elsie Widdowson Lab, Cambridge, England;Univ Eastern Finland, Inst Clin Med, Internal Med, Kuopio, Finland.
    Laakso, Markku
    Kuopio Univ Hosp, Dept Med, Kuopio, Finland.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lin, Hung-Ju
    Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan.
    McKnight, Barbara
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA.
    Rajaobelina, Kalina
    Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala Univ, Dept Publ Hlth & Caring Sci, Clin Nutr & Metab, Uppsala, Sweden.
    Robinson, Jennifer G.
    Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA;Univ Iowa, Dept Med, Coll Publ Hlth, Iowa City, IA 52242 USA.
    Samieri, Cecilia
    Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France.
    Siscovick, David S.
    New York Acad Med, New York, NY USA.
    Soedamah-Muthu, Sabita S.
    Tilburg Univ, Ctr Res Psychol Somat Dis, Dept Med & Clin Psychol, Tilburg, Netherlands.
    Sotoodehnia, Nona
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Sun, Qi
    Harvard TH Chan Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA USA.
    Tsai, Michael Y.
    Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA.
    Uusitupa, Matti
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland.
    Wagenknecht, Lynne E.
    Wake Forest Sch Med, Publ Hlth Sci, Winston Salem, NC USA.
    Wareham, Nick J.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England.
    Wu, Jason H. Y.
    Univ New South Wales, George Inst Global Hlth, Sydney, NSW, Australia;Univ New South Wales, Fac Med, Sydney, NSW, Australia.
    Micha, Renata
    Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA.
    Forouhi, Nita G.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England.
    Lemaitre, Rozenn N.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Mozaffarian, Dariush
    Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA.
    Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 10, article id e1002670Article in journal (Refereed)
    Abstract [en]

    Background We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15: 0 and 17: 0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D). Methods and findings Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, tri-glycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men ((pinteraction) < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist. Conclusions In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.

  • 30. Imamura, Fumiaki
    et al.
    Sharp, Stephen J.
    Koulman, Albert
    Schulze, Matthias B.
    Kröger, Janine
    Griffin, Julian L.
    Huerta, José M.
    Guevara, Marcela
    Sluijs, Ivonne
    Agudo, Antonio
    Ardanaz, Eva
    Balkau, Beverley
    Boeing, Heiner
    Chajes, Veronique
    Dahm, Christina C.
    Dow, Courtney
    Fagherazzi, Guy
    Feskens, Edith J. M.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine. Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
    Gavrila, Diana
    Gunter, Marc
    Kaaks, Rudolf
    Key, Timothy J.
    Khaw, Kay-Tee
    Kuehn, Tilman
    Melander, Olle
    Molina-Portillo, Elena
    Nilsson, Peter M.
    Olsen, Anja
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sieri, Sabina
    Sacerdote, Carlotta
    Slimani, Nadia
    Spijkerman, Annemieke M. W.
    Tjønneland, Anne
    Tumino, Rosario
    van der Schouw, Yvonne T.
    Langenberg, Claudia
    Riboli, Elio
    Forouhi, Nita G.
    Wareham, Nick J.
    A combination of plasma phospholipid fatty acids and its association with incidence of type 2 diabetes: The EPIC-InterAct case-cohort study2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 10, article id e1002409Article in journal (Refereed)
    Abstract [en]

    Background Combinations of multiple fatty acids may influence cardiometabolic risk more than single fatty acids. The association of a combination of fatty acids with incident type 2 diabetes (T2D) has not been evaluated.

    Methods and findings We measured plasma phospholipid fatty acids by gas chromatography in 27,296 adults, including 12,132 incident cases of T2D, over the follow-up period between baseline (1991-1998) and 31 December 2007 in 8 European countries in EPIC-InterAct, a nested casecohort study. The first principal component derived by principal component analysis of 27 individual fatty acids (mole percentage) was the main exposure (subsequently called the fatty acid pattern score [FA-pattern score]). The FA-pattern score was partly characterised by high concentrations of linoleic acid, stearic acid, odd-chain fatty acids, and very-long-chain saturated fatty acids and low concentrations of.-linolenic acid, palmitic acid, and long-chain monounsaturated fatty acids, and it explained 16.1% of the overall variability of the 27 fatty acids. Based on country-specific Prentice-weighted Cox regression and random-effects meta-analysis, the FA-pattern score was associated with lower incident T2D. Comparing the top to the bottom fifth of the score, the hazard ratio of incident T2D was 0.23 (95% CI 0.19-0.29) adjusted for potential confounders and 0.37 (95% CI 0.27-0.50) further adjusted for metabolic risk factors. The association changed little after adjustment for individual fatty acids or fatty acid subclasses. In cross-sectional analyses relating the FA-pattern score to metabolic, genetic, and dietary factors, the FA-pattern score was inversely associated with adiposity, triglycerides, liver enzymes, C-reactive protein, a genetic score representing insulin resistance, and dietary intakes of soft drinks and alcohol and was positively associated with high-density-lipoprotein cholesterol and intakes of polyunsaturated fat, dietary fibre, and coffee (p < 0.05 each). Limitations include potential measurement error in the fatty acids and other model covariates and possible residual confounding.

    Conclusions A combination of individual fatty acids, characterised by high concentrations of linoleic acid, odd-chain fatty acids, and very long-chain fatty acids, was associated with lower incidence of T2D. The specific fatty acid pattern may be influenced by metabolic, genetic, and dietary factors.

  • 31.
    Johansson, Mattias
    et al.
    IARC, Lyon, France.
    Carreras-Torres, Robert
    IARC, Lyon, France.
    Scelo, Ghislaine
    IARC, Lyon, France.
    Purdue, Mark P.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Mariosa, Daniela
    IARC, Lyon, France.
    Muller, David C.
    Imperial Coll, London, England.
    Timpson, Nicolas J.
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England.
    Haycock, Philip C.
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England.
    Brown, Kevin M.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Wang, Zhaoming
    St Jude Childrens Res Hosp, Memphis, TN USA.
    Ye, Yuanqing
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX USA.
    Hofmann, Jonathan N.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Foll, Matthieu
    IARC, Lyon, France.
    Gaborieau, Valerie
    IARC, Lyon, France.
    Machiela, Mitchell J.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Colli, Leandro M.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Li, Peng
    IARC, Lyon, France;Max Planck Inst Demog Res, Rostock, Germany.
    Garnier, Jean-Guillaume
    Ctr Energie Atom & Energies Alternat, Inst Genom, Ctr Natl Genotypage, Evry, France; Ctr Etud Polymorphisme Humain, Fdn Jean Dausset, Paris, France.
    Blanche, Helene
    Ctr Energie Atom & Energies Alternat, Inst Genom, Ctr Natl Genotypage, Evry, France.
    Boland, Anne
    Ctr Energie Atom & Energies Alternat, Inst Genom, Ctr Natl Genotypage, Evry, France.
    Burdette, Laurie
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Prokhortchouk, Egor
    Russian Acad Sci, Fed Res Ctr Fundamentals Biotechnol, Moscow, Russia.
    Skryabin, Konstantin G.
    Russian Acad Sci, Fed Res Ctr Fundamentals Biotechnol, Moscow, Russia; Kurchatov Sci Ctr, Moscow, Russia.
    Yeager, Meredith
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Radojevic-Skodric, Sanja
    Univ Belgrade Sch Med, Inst Pathol, Belgrade, Serbia; Clin Ctr Serbia, Clin Urol, Belgrade, Serbia.
    Ognjanovic, Simona
    Mayo Clin, Grad Sch Biomed Sci, Rochester, MN USA; IOCPR, Belgrade, Serbia.
    Foretova, Lenka
    Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic.
    Holcatova, Ivana
    Charles Univ Prague, Fac Med 2, Inst Publ Hlth & Prevent Med, Prague, Czech Republic.
    Janout, Vladimir
    Palacky Univ, Fac Med, Dept Prevent Med, Olomouc, Czech Republic.
    Mates, Dana
    Natl Inst Publ Hlth, Bucharest, Romania.
    Mukeriya, Anush
    Russian NN Blokhin Canc Res Ctr, Moscow, Russia.
    Rascu, Stefan
    Carol Davila Univ Med & Pharm, Th Burghele Hosp, Bucharest, Romania.
    Zaridze, David
    Russian NN Blokhin Canc Res Ctr, Moscow, Russia.
    Bencko, Vladimir
    Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic.
    Cybulski, Cezary
    Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland.
    Fabianova, Eleonora
    Reg Author Publ Hlth Banska Bystr, Banska Bystrica, Slovakia.
    Jinga, Viorel
    Carol Davila Univ Med & Pharm, Th Burghele Hosp, Bucharest, Romania.
    Lissowska, Jolanta
    M Sklodowska Curie Canc Ctr, Warsaw, Poland; Inst Oncol, Warsaw, Poland.
    Lubinski, Jan
    Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland.
    Navratilova, Marie
    Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic.
    Rudnai, Peter
    Natl Publ Hlth Ctr, Natl Directorate Environm Hlth, Budapest, Hungary.
    Benhamou, Simone
    INSERM, U946, Paris, France; CNRS, Inst Gustave Roussy, UMR 8200, Villejuif, France.
    Cancel-Tassin, Geraldine
    CeRePP, Paris, France; UPMC Univ Paris 06, Inst Univ Cancerol, GRC 5, Paris, France.
    Cussenot, Olivier
    CeRePP, Paris, France; UPMC Univ Paris 06, Inst Univ Cancerol, GRC 5, Paris, France; Hopitaux Univ Est Parisien Tenon, AP HP, Dept Urol, Paris, France.
    Weiderpass, Elisabete
    Canc Registry Norway, Inst Population Based Canc Res, Dept Res, Oslo, Norway; Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden; Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland; Arctic Univ Norway, Univ Tromso, Dept Community Med, Tromso, Norway.
    Ljungberg, Borje
    Umeå Univ, Dept Surg & Perioperat Sci Urol & Androl, Umeå, Sweden.
    Sitaram, Raviprakash Tumkur
    Umeå Univ, Dept Surg & Perioperat Sci Urol & Androl, Umeå, Sweden.
    Häggström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Umeå Univ, Dept Biobank Res, Umeå, Sweden.
    Bruinsma, Fiona
    Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia.
    Jordan, Susan J.
    QIMR Berghofer Med Res Inst, Herston, Qld, Australia; Univ Queensland, Sch Publ Hlth, Brisbane, Qld, Australia.
    Severi, Gianluca
    Univ Paris Saclay, Univ Paris Sud, Hlth Generat Team, CESP,INSERM,Fac Med,UVSQ,Gustave Roussy, Villejuif, France; Human Genet Fdn HuGeF, Turin, Italy.
    Winship, Ingrid
    Univ Melbourne, Royal Melbourne Hosp, Dept Med, Melbourne, Vic, Australia.
    Hveem, Kristian
    Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway.
    Vatten, Lars J.
    Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth & Gen Practice, Trondheim, Norway.
    Fletcher, Tony
    Univ London, London Sch Hyg & Trop Med, London, England.
    Larsson, Susanna C.
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Wolk, Alicja
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Banks, Rosamonde E.
    Univ Leeds, St Jamess Univ Hosp, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England.
    Selby, Peter J.
    Imperial Coll London, St Marys Hosp, Div Surg, Natl Inst Hlth Res Diagnost Evidence Cooperat, London, England.
    Easton, Douglas F.
    Univ Cambridge, Dept Oncol, Cambridge, England; Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.
    Andreotti, Gabriella
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Freeman, Laura E. Beane
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Koutros, Stella
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Mannisto, Satu
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Weinstein, Stephanie
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Clark, Peter E.
    Vanderbilt Ingram Canc Ctr, Nashville, TN USA.
    Edwards, Todd L.
    Vanderbilt Genet Inst, Vanderbilt Ingram Canc Ctr, Div Epidemiol, Dept Med, Nashville, TN USA.
    Lipworth, Loren
    Vanderbilt Ingram Canc Ctr, Nashville, TN USA.
    Gapstur, Susan M.
    Amer Canc Soc, Atlanta, GA 30329 USA.
    Stevens, Victoria L.
    Amer Canc Soc, Atlanta, GA 30329 USA.
    Carol, Hallie
    Dana Farber Canc Inst, Boston, MA 02115 USA.
    Freedman, Matthew L.
    Dana Farber Canc Inst, Boston, MA 02115 USA.
    Pomerantz, Mark M.
    Dana Farber Canc Inst, Boston, MA 02115 USA.
    Cho, Eunyoung
    Brown Univ, Providence, RI 02912 USA.
    Wilson, Kathryn M.
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA.
    Gaziano, J. Michael
    Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA.
    Sesso, Howard D.
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA; Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.
    Freedman, Neal D.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Parker, Alexander S.
    Mayo Clin, Dept Hlth Sci Res, Jacksonville, FL 32224 USA.
    Eckel-Passow, Jeanette E.
    Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA.
    Huang, Wen-Yi
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Kahnoski, Richard J.
    Spectrum Hlth, Div Urol, Grand Rapids, MI USA.
    Lane, Brian R.
    Spectrum Hlth, Div Urol, Grand Rapids, MI USA; Michigan State Univ, Coll Human Med, Grand Rapids, MI USA.
    Noyes, Sabrina L.
    Van Andel Res Inst, Ctr Canc Genom & Quantitat Biol, Grand Rapids, MI USA; Spectrum Hlth, Grand Rapids, MI USA.
    Petillo, David
    Van Andel Res Inst, Ctr Canc Genom & Quantitat Biol, Grand Rapids, MI USA; Ferris State Univ, Diagnost Program, Grand Rapids, MI USA.
    Teh, Bin Tean
    Van Andel Res Inst, Ctr Canc Genom & Quantitat Biol, Grand Rapids, MI USA; Natl Univ Singapore, Med Sch, Program Canc & Stem Cell Biol, Duke Natl, Singapore, Singapore; ASTAR, Inst Mol & Cell Biol, Singapore, Singapore; Natl Canc Ctr Singapore, Div Med Sci, Lab Canc Epigenome, Singapore, Singapore; Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore.
    Peters, Ulrike
    Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA.
    White, Emily
    Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA.
    Anderson, Garnet L.
    Fred Hutchinson Canc Res Ctr, WHI Clin Coordinating Ctr, 1124 Columbia St, Seattle, WA 98104 USA.
    Johnson, Lisa
    Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA.
    Luo, Juhua
    Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN USA.
    Buring, Julie
    Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA; Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.
    Lee, I-Min
    Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA; Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.
    Chow, Wong-Ho
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA.
    Moore, Lee E.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Eisen, Timothy
    Univ Cambridge, Cambridge, England.
    Henrion, Marc
    Inst Canc Res, London, England; Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.
    Larkin, James
    Royal Marsden NHS Fdn Trust, London, England.
    Barman, Poulami
    Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA.
    Leibovich, Bradley C.
    Mayo Clin, Dept Urol, Rochester, MN USA.
    Choueiri, Toni K.
    Dana Farber Canc Inst, Boston, MA 02115 USA.
    Lathrop, G. Mark
    McGill Univ, Montreal, PQ, Canada;Genome Quebec Innovat Ctr, Montreal, PQ, Canada.
    Deleuze, Jean-Francois
    Ctr Energie Atom & Energies Alternat, Inst Genom, Ctr Natl Genotypage, Evry, France; Ctr Etud Polymorphisme Humain, Fdn Jean Dausset, Paris, France.
    Gunter, Marc
    IARC, Lyon, France.
    McKay, James D.
    IARC, Lyon, France.
    Wu, Xifeng
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA.
    Houlston, Richard S.
    Inst Canc Res, London, England.
    Chanock, Stephen J.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Relton, Caroline
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England; Univ Bristol, Sch Social & Community Med, Bristol, Avon, England.
    Richards, J. Brent
    McGill Univ, Jewish Gen Hosp, Dept Med, Montreal, PQ, Canada;McGill Univ, Jewish Gen Hosp, Dept Human Genet, Montreal, PQ, Canada;McGill Univ, Jewish Gen Hosp, Dept Epidemiol & Biostat, Montreal, PQ, Canada.
    Martin, Richard M.
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England; Univ Bristol, Sch Social & Community Med, Bristol, Avon, England; Univ Bristol, Univ Hosp Bristol NHS Fdn Trust, Natl Inst Hlth Res, Bristol Nutr Biomed Res Unit, Bristol, Avon, England.
    Smith, George Davey
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England; Univ Bristol, Sch Social & Community Med, Bristol, Avon, England.
    Brennan, Paul
    IARC, Lyon, France.
    The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study2019In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, no 1, article id e1002724Article in journal (Refereed)
    Abstract [en]

    Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

    Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.

    Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

  • 32. Johansson, Mattias
    et al.
    Carreras-Torres, Robert
    Scelo, Ghislaine
    Purdue, Mark P.
    Mariosa, Daniela
    Muller, David C.
    Timpson, Nicolas J.
    Haycock, Philip C.
    Brown, Kevin M.
    Wang, Zhaoming
    Ye, Yuanqing
    Hofmann, Jonathan N.
    Foll, Matthieu
    Gaborieau, Valerie
    Machiela, Mitchell J.
    Colli, Leandro M.
    Li, Peng
    Garnier, Jean-Guillaume
    Blanche, Helene
    Boland, Anne
    Burdette, Laurie
    Prokhortchouk, Egor
    Skryabin, Konstantin G.
    Yeager, Meredith
    Radojevic-Skodric, Sanja
    Ognjanovic, Simona
    Foretova, Lenka
    Holcatova, Ivana
    Janout, Vladimir
    Mates, Dana
    Mukeriya, Anush
    Rascu, Stefan
    Zaridze, David
    Bencko, Vladimir
    Cybulski, Cezary
    Fabianova, Eleonora
    Jinga, Viorel
    Lissowska, Jolanta
    Lubinski, Jan
    Navratilova, Marie
    Rudnai, Peter
    Benhamou, Simone
    Cancel-Tassin, Geraldine
    Cussenot, Olivier
    Weiderpass, Elisabete
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tumkur Sitaram, Raviprakash
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Sweden.
    Bruinsma, Fiona
    Jordan, Susan J
    Severi, Gianluca
    Winship, Ingrid
    Hveem, Kristian
    Vatten, Lars J
    Fletcher, Tony
    Larsson, Susanna C
    Wolk, Alicja
    Banks, Rosamonde E
    Selby, Peter J
    Easton, Douglas F
    Andreotti, Gabriella
    Beane Freeman, Laura E
    Koutros, Stella
    Männistö, Satu
    Weinstein, Stephanie
    Clark, Peter E
    Edwards, Todd L
    Lipworth, Loren
    Gapstur, Susan M
    Stevens, Victoria L
    Carol, Hallie
    Freedman, Matthew L
    Pomerantz, Mark M
    Cho, Eunyoung
    Wilson, Kathryn M
    Gaziano, J Michael
    Sesso, Howard D
    Freedman, Neal D
    Parker, Alexander S
    Eckel-Passow, Jeanette E
    Huang, Wen-Yi
    Kahnoski, Richard J
    Lane, Brian R
    Noyes, Sabrina L
    Petillo, David
    Teh, Bin Tean
    Peters, Ulrike
    White, Emily
    Anderson, Garnet L
    Johnson, Lisa
    Luo, Juhua
    Buring, Julie
    Lee, I-Min
    Chow, Wong-Ho
    Moore, Lee E
    Eisen, Timothy
    Henrion, Marc
    Larkin, James
    Barman, Poulami
    Leibovich, Bradley C
    Choueiri, Toni K
    Lathrop, G Mark
    Deleuze, Jean-Francois
    Gunter, Marc
    McKay, James D
    Wu, Xifeng
    Houlston, Richard S
    Chanock, Stephen J
    Relton, Caroline
    Richards, J Brent
    Martin, Richard M
    Davey Smith, George
    Brennan, Paul
    The influence of obesity-related factors in the etiology of renal cell carcinoma: A mendelian randomization study2019In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, no 1, article id e1002724Article in journal (Refereed)
    Abstract [en]

    Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

    Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.

    Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

  • 33.
    Karlsson, Lars
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Nilsson, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Vikbolandet.
    Bång, Magnus
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, Faculty of Science & Engineering.
    Nilsson, Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Charitakis, Emmanouil
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Janzon, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    A clinical decision support tool for improving adherence to guidelines on anticoagulant therapy in patients with atrial fibrillation at risk of stroke: A cluster-randomized trial in a Swedish primary care setting (the CDS-AF study)2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 3, article id e1002528Article in journal (Refereed)
    Abstract [en]

    Background

    Atrial fibrillation (AF) is associated with substantial morbidity, in particular stroke. Despite good evidence for the reduction of stroke risk with anticoagulant therapy, there remains significant undertreatment. The main aim of the current study was to investigate whether a clinical decision support tool (CDS) for stroke prevention integrated in the electronic health record could improve adherence to guidelines for stroke prevention in patients with AF.

    Methods and findings

    We conducted a cluster-randomized trial where all 43 primary care clinics in the county of Östergötland, Sweden (population 444,347), were randomized to be part of the CDS intervention or to serve as controls. The CDS produced an alert for physicians responsible for patients with AF and at increased risk for thromboembolism (according to the CHA2DS2-VASc algorithm) without anticoagulant therapy. The primary endpoint was adherence to guidelines after 1 year. After randomization, there were 22 and 21 primary care clinics in the CDS and control groups, respectively. There were no significant differences in baseline adherence to guidelines regarding anticoagulant therapy between the 2 groups (CDS group 70.3% [5,186/7,370; 95% CI 62.9%–77.7%], control group 70.0% [4,187/6,009; 95% CI 60.4%–79.6%], p = 0.83). After 12 months, analysis with linear regression with adjustment for primary care clinic size and adherence to guidelines at baseline revealed a significant increase in guideline adherence in the CDS (73.0%, 95% CI 64.6%–81.4%) versus the control group (71.2%, 95% CI 60.8%–81.6%, p = 0.013, with a treatment effect estimate of 0.016 [95% CI 0.003–0.028]; number of patients with AF included in the final analysis 8,292 and 6,508 in the CDS and control group, respectively). Over the study period, there was no difference in the incidence of stroke, transient ischemic attack, or systemic thromboembolism in the CDS group versus the control group (49 [95% CI 43–55] per 1,000 patients with AF in the CDS group compared to 47 [95% CI 39–55] per 1,000 patients with AF in the control group, p = 0.64). Regarding safety, the CDS group had a lower incidence of significant bleeding, with events in 12 (95% CI 9–15) per 1,000 patients with AF compared to 16 (95% CI 12–20) per 1,000 patients with AF in the control group (p = 0.04). Limitations of the study design include that the analysis was carried out in a catchment area with a high baseline adherence rate, and issues regarding reproducibility to other regions.

    Conclusions

    The present study demonstrates that a CDS can increase guideline adherence for anticoagulant therapy in patients with AF. Even though the observed difference was small, this is the first randomized study to our knowledge indicating beneficial effects with a CDS in patients with AF.

  • 34.
    Karmali, Kunal N.
    et al.
    Northwestern Univ, Dept Med, Chicago, IL 60611 USA..
    Lloyd-Jones, Donald M.
    Northwestern Univ, Dept Med, Chicago, IL 60611 USA..
    van der Leeuw, Joep
    Univ Med Ctr Utrecht, Dept Vasc Med, Utrecht, Netherlands..
    Goff, David C., Jr.
    NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA..
    Yusuf, Salim
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada..
    Zanchetti, Alberto
    Ist Auxol Italiano, Milan, Italy..
    Glasziou, Paul
    Bond Univ, Ctr Res Evidence Based Practice, Robina, Australia..
    Jackson, Rodney
    Univ Auckland, Sch Populat Hlth, Fac Med & Hlth Sci, Auckland, New Zealand..
    Woodward, Mark
    Univ Oxford, George Inst Global Hlth, Oxford, England.;George Inst Global Hlth, Sydney, NSW, Australia..
    Rodgers, Anthony
    George Inst Global Hlth, Sydney, NSW, Australia..
    Neal, Bruce C.
    George Inst Global Hlth, Sydney, NSW, Australia..
    Berge, Eivind
    Oslo Univ Hosp, Dept Cardiol, Oslo, Norway..
    Teo, Koon
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada..
    Davis, Barry R.
    Univ Texas Dallas, Sch Publ Hlth, Dallas, TX USA..
    Chalmers, John
    George Inst Global Hlth, Sydney, NSW, Australia..
    Pepine, Carl
    Univ Florida, Div Cardiovasc Med, Gainesville, FL USA..
    Rahimi, Kazem
    Univ Oxford, George Inst Global Hlth, Oxford, England..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Blood pressure-lowering treatment strategies based on cardiovascular risk versus blood pressure: A meta-analysis of individual participant data2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 3, article id e1002538Article in journal (Refereed)
    Abstract [en]

    Background: Clinical practice guidelines have traditionally recommended blood pressure treatment based primarily on blood pressure thresholds. In contrast, using predicted cardiovascular risk has been advocated as a more effective strategy to guide treatment decisions for cardiovascular disease (CVD) prevention. We aimed to compare outcomes from a blood pressure-lowering treatment strategy based on predicted cardiovascular risk with one based on systolic blood pressure (SBP) level.

    Methods and findings: We used individual participant data from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) from 1995 to 2013. Trials randomly assigned participants to either blood pressure-lowering drugs versus placebo or more intensive versus less intensive blood pressure-lowering regimens. We estimated 5-y risk of CVD events using a multivariable Weibull model previously developed in this dataset. We compared the two strategies at specific SBP thresholds and across the spectrum of risk and blood pressure levels studied in BPLTTC trials. The primary outcome was number of CVD events avoided per persons treated. We included data from 11 trials (47,872 participants). During a median of 4.0 y of follow-up, 3,566 participants (7.5%) experienced a major cardiovascular event. Areas under the curve comparing the two treatment strategies throughout the range of possible thresholds for CVD risk and SBP demonstrated that, on average, a greater number of CVD events would be avoided for a given number of persons treated with the CVD risk strategy compared with the SBP strategy (area under the curve 0.71 [95% confidence interval (CI) 0.70-0.72] for the CVD risk strategy versus 0.54 [95% CI 0.53-0.55] for the SBP strategy). Compared with treating everyone with SBP >= 150 mmHg, a CVD risk strategy would require treatment of 29% (95% CI 26%-31%) fewer persons to prevent the same number of events or would prevent 16% (95% CI 14%-18%) more events for the same number of persons treated. Compared with treating everyone with SBP >= 140 mmHg, a CVD risk strategy would require treatment of 3.8% (95% CI 12.5% fewer to 7.2% more) fewer persons to prevent the same number of events or would prevent 3.1% (95% CI 1.5%-5.0%) more events for the same number of persons treated, although the former estimate was not statistically significant. In subgroup analyses, the CVD risk strategy did not appear to be more beneficial than the SBP strategy in patients with diabetes mellitus or established CVD.

    Conclusions: A blood pressure-lowering treatment strategy based on predicted cardiovascular risk is more effective than one based on blood pressure levels alone across a range of thresholds. These results support using cardiovascular risk assessment to guide blood pressure treatment decision-making in moderate- to high-risk individuals, particularly for primary prevention.

  • 35. Kilpeläinen, Tuomas O
    et al.
    Qi, Lu
    Brage, Soren
    Sharp, Stephen J
    Sonestedt, Emily
    Demerath, Ellen
    Ahmad, Tariq
    Mora, Samia
    Kaakinen, Marika
    Sandholt, Camilla Helene
    Holzapfel, Christina
    Autenrieth, Christine S
    Hyppönen, Elina
    Cauchi, Stéphane
    He, Meian
    Kutalik, Zoltan
    Kumari, Meena
    Stančáková, Alena
    Meidtner, Karina
    Balkau, Beverley
    Tan, Jonathan T
    Mangino, Massimo
    Timpson, Nicholas J
    Song, Yiqing
    Zillikens, M Carola
    Jablonski, Kathleen A
    Garcia, Melissa E
    Johansson, Stefan
    Bragg-Gresham, Jennifer L
    Wu, Ying
    van Vliet-Ostaptchouk, Jana V
    Onland-Moret, N Charlotte
    Zimmermann, Esther
    Rivera, Natalia V
    Tanaka, Toshiko
    Stringham, Heather M
    Silbernagel, Günther
    Kanoni, Stavroula
    Feitosa, Mary F
    Snitker, Soren
    Ruiz, Jonatan R
    Metter, Jeffery
    Larrad, Maria Teresa Martinez
    Atalay, Mustafa
    Hakanen, Maarit
    Amin, Najaf
    Cavalcanti-Proença, Christine
    Grøntved, Anders
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Jansson, John-Olov
    Kuusisto, Johanna
    Kähönen, Mika
    Lutsey, Pamela L
    Nolan, John J
    Palla, Luigi
    Pedersen, Oluf
    Pérusse, Louis
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Scott, Robert A
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sovio, Ulla
    Tammelin, Tuija H
    Rönnemaa, Tapani
    Lakka, Timo A
    Uusitupa, Matti
    Rios, Manuel Serrano
    Ferrucci, Luigi
    Bouchard, Claude
    Meirhaeghe, Aline
    Fu, Mao
    Walker, Mark
    Borecki, Ingrid B
    Dedoussis, George V
    Fritsche, Andreas
    Ohlsson, Claes
    Boehnke, Michael
    Bandinelli, Stefania
    van Duijn, Cornelia M
    Ebrahim, Shah
    Lawlor, Debbie A
    Gudnason, Vilmundur
    Harris, Tamara B
    Sørensen, Thorkild I A
    Mohlke, Karen L
    Hofman, Albert
    Uitterlinden, André G
    Tuomilehto, Jaakko
    Lehtimäki, Terho
    Raitakari, Olli
    Isomaa, Bo
    Njølstad, Pål R
    Florez, Jose C
    Liu, Simin
    Ness, Andy
    Spector, Timothy D
    Tai, E Shyong
    Froguel, Philippe
    Boeing, Heiner
    Laakso, Markku
    Marmot, Michael
    Bergmann, Sven
    Power, Chris
    Khaw, Kay-Tee
    Chasman, Daniel
    Ridker, Paul
    Hansen, Torben
    Monda, Keri L
    Illig, Thomas
    Järvelin, Marjo-Riitta
    Wareham, Nicholas J
    Hu, Frank B
    Groop, Leif C
    Orho-Melander, Marju
    Ekelund, Ulf
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Loos, Ruth J F
    Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children2011In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 8, no 11, p. e1001116-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).

    METHODS AND FINDINGS: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction)  = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio  = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio  = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents.

    CONCLUSIONS: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.

  • 36. Kloprogge, Frank
    et al.
    Workman, Lesley
    Borrmann, Steffen
    Tékété, Mamadou
    Lefèvre, Gilbert
    Hamed, Kamal
    Piola, Patrice
    Ursing, Johan
    Kofoed, Poul Erik
    Mårtensson, Andreas
    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), International Child Health and Nutrition.
    Ngasala, Billy
    Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
    Björkman, Anders
    Ashton, Michael
    Friberg Hietala, Sofia
    Aweeka, Francesca
    Parikh, Sunil
    Mwai, Leah
    Davis, Timothy M. E.
    Karunajeewa, Harin
    Salman, Sam
    Checchi, Francesco
    Fogg, Carole
    Newton, Paul N.
    Mayxay, Mayfong
    Deloron, Philippe
    Faucher, Jean François
    Nosten, François
    Ashley, Elizabeth A.
    McGready, Rose
    van Vugt, Michele
    Proux, Stephane
    Price, Ric N.
    Karbwang, Juntra
    Ezzet, Farkad
    Bakshi, Rajesh
    Stepniewska, Kasia
    White, Nicholas J.
    Guerin, Philippe J.
    Barnes, Karen I.
    Tarning, Joel
    Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 6, article id e1002579Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations.

    METHODS AND FINDINGS: A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7.

    CONCLUSIONS: Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

  • 37.
    Lachat, Carl
    et al.
    University of Ghent, Belgium; Institute Trop Med, Belgium.
    Hawwash, Dana
    University of Ghent, Belgium.
    Ocke, Marga C.
    National Institute Public Health and Environm, Netherlands.
    Berg, Christina
    University of Gothenburg, Sweden.
    Forsum, Elisabet
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Hornell, Agneta
    Umeå University, Sweden.
    Larsson, Christel
    University of Gothenburg, Sweden.
    Sonestedt, Emily
    Lund University, Sweden.
    Wirfalt, Elisabet
    Lund University, Sweden.
    Åkesson, Agneta
    Karolinska Institute, Sweden.
    Kolsteren, Patrick
    University of Ghent, Belgium; Institute Trop Med, Belgium.
    Byrnes, Graham
    Int Agency Research Canc, France.
    De Keyzer, Willem
    University of Coll Ghent, Belgium.
    Van Camp, John
    University of Ghent, Belgium.
    Cade, Janet E.
    University of Leeds, England.
    Slimani, Nadia
    Int Agency Research Canc, France.
    Cevallos, Myriam
    University of Bern, Switzerland; University of Bern, Switzerland.
    Egger, Matthias
    University of Bern, Switzerland.
    Huybrechts, Inge
    Int Agency Research Canc, France.
    Strengthening the Reporting of Observational Studies in Epidemiology-Nutritional Epidemiology (STROBE-nut): An Extension of the STROBE Statement2016In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 13, no 6, p. e1002036-Article, review/survey (Refereed)
    Abstract [en]

    Background Concerns have been raised about the quality of reporting in nutritional epidemiology. Research reporting guidelines such as the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement can improve quality of reporting in observational studies. Herein, we propose recommendations for reporting nutritional epidemiology and dietary assessment research by extending the STROBE statement into Strengthening the Reporting of Observational Studies in Epidemiology-Nutritional Epidemiology (STROBE-nut). Methods and Findings Recommendations for the reporting of nutritional epidemiology and dietary assessment research were developed following a systematic and consultative process, coordinated by a multidisciplinary group of 21 experts. Consensus on reporting guidelines was reached through a three-round Delphi consultation process with 53 external experts. In total, 24 recommendations for nutritional epidemiology were added to the STROBE checklist. Conclusion When used appropriately, reporting guidelines for nutritional epidemiology can contribute to improve reporting of observational studies with a focus on diet and health.

  • 38. Lachat, Carl
    et al.
    Hawwash, Dana
    Ocke, Marga C.
    Berg, Christina
    Forsum, Elisabet
    Hörnell, Agneta
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Larsson, Christel
    Sonestedt, Emily
    Wirfalt, Elisabet
    Akesson, Agneta
    Kolsteren, Patrick
    Byrnes, Graham
    De Keyzer, Willem
    Van Camp, John
    Cade, Janet E.
    Slimani, Nadia
    Cevallos, Myriam
    Egger, Matthias
    Huybrechts, Inge
    Strengthening the Reporting of Observational Studies in Epidemiology-Nutritional Epidemiology (STROBE-nut): An Extension of the STROBE Statement2016In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 13, no 6, article id e1002036Article in journal (Refereed)
    Abstract [en]

    Background: Concerns have been raised about the quality of reporting in nutritional epidemiology. Research reporting guidelines such as the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement can improve quality of reporting in observational studies. Herein, we propose recommendations for reporting nutritional epidemiology and dietary assessment research by extending the STROBE statement into Strengthening the Reporting of Observational Studies in Epidemiology—Nutritional Epidemiology (STROBE-nut).

    Methods and Findings: Recommendations for the reporting of nutritional epidemiology and dietary assessment research were developed following a systematic and consultative process, coordinated by a multidisciplinary group of 21 experts. Consensus on reporting guidelines was reached through a three-round Delphi consultation process with 53 external experts. In total, 24 recommendations for nutritional epidemiology were added to the STROBE checklist.

    Conclusion: When used appropriately, reporting guidelines for nutritional epidemiology can contribute to improve reporting of observational studies with a focus on diet and health.

  • 39. Langenberg, Claudia
    et al.
    Sharp, Stephen J.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Lund University, Malmö, Sweden.
    Scott, Robert A.
    Deloukas, Panos
    Forouhi, Nita G.
    Froguel, Philippe
    Groop, Leif C.
    Hansen, Torben
    Palla, Luigi
    Pedersen, Oluf
    Schulze, Matthias B.
    Tormo, Maria-Jose
    Wheeler, Eleanor
    Agnoli, Claudia
    Arriola, Larraitz
    Barricarte, Aurelio
    Boeing, Heiner
    Clarke, Geraldine M.
    Clavel-Chapelon, Francoise
    Duell, Eric J.
    Fagherazzi, Guy
    Kaaks, Rudolf
    Kerrison, Nicola D.
    Key, Timothy J.
    Khaw, Kay Tee
    Kroeger, Janine
    Lajous, Martin
    Morris, Andrew P.
    Navarro, Carmen
    Nilsson, Peter M.
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Quiros, J. Ramon
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Slimani, Nadia
    Spijkerman, Annemieke M. W.
    Tumino, Rosario
    van der A, Daphne L.
    van der Schouw, Yvonne T.
    Barroso, Ines
    McCarthy, Mark I.
    Riboli, Elio
    Wareham, Nicholas J.
    Gene-Lifestyle Interaction and Type 2 Diabetes: the EPIC InterAct Case-Cohort Study2014In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 11, no 5, article id e1001647Article in journal (Refereed)
    Abstract [en]

    Background: Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. Methods and Findings: The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction = 1.20x10(-4)). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction = 1.50x10(-3)) and waist circumference (p for interaction = 7.49x10(-9)). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score. Conclusions: The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this subgroup is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.

  • 40. Langenberg, Claudia
    et al.
    Sharp, Stephen J.
    Schulze, Matthias B
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Overvad, Kim
    Forouhi, Nita G
    Spranger, Joachim
    Drogan, Dagmar
    Maria Huerta, Jose
    Arriola, Larraitz
    de Lauzon-Guillan, Blandine
    Tormo, Maria-Jose
    Ardanaz, Eva
    Balkau, Beverley
    Beulens, Joline WJ
    Boeing, Heiner
    Bueno-de-Mesquita, H Bas
    Clavel-Chapelon, Francoise
    Crowe, Francesca L
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gonzalez, Carlos A
    Grioni, Sara
    Halkjaer, Jytte
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Kaaks, Rudolf
    Kerrison, Nicola D
    Key, Timothy J
    Khaw, Kay Tee
    Mattiello, Amalia
    Nilsson, Peter
    Norat, Teresa
    Palla, Luigi
    Palli, Domenico
    Panico, Salvatore
    Ramon Quiros, J
    Romaguera, Dora
    Romieu, Isabelle
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Slimani, Nadia
    Sluijs, Ivonne
    Spijkerman, Annemieke MW
    Teucher, Birgit
    Tjonneland, Anne
    Tumino, Rosario
    Daphne, L van der A
    van der Schouw, Yvonne T
    Feskens, Edith JM
    Riboli, Elio
    Wareham, Nicholas J
    Long-term risk of incident type 2 diabetes and measures of overall and regional obesity: the EPIC-interact case-cohort study2012In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 9, no 6, p. e1001230-Article in journal (Refereed)
    Abstract [en]

    Background: Waist circumference (WC) is a simple and reliable measure of fat distribution that may add to the prediction of type 2 diabetes (T2D), but previous studies have been too small to reliably quantify the relative and absolute risk of future diabetes by WC at different levels of body mass index (BMI).

    Methods and Findings: The prospective InterAct case-cohort study was conducted in 26 centres in eight European countries and consists of 12,403 incident T2D cases and a stratified subcohort of 16,154 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. We used Prentice-weighted Cox regression and random effects meta-analysis methods to estimate hazard ratios for T2D. Kaplan-Meier estimates of the cumulative incidence of T2D were calculated. BMI and WC were each independently associated with T2D, with WC being a stronger risk factor in women than in men. Risk increased across groups defined by BMI and WC; compared to low normal weight individuals (BMI 18.5-22.4 kg/m(2)) with a low WC (< 94/80 cm in men/women), the hazard ratio of T2D was 22.0 (95% confidence interval 14.3; 33.8) in men and 31.8 (25.2; 40.2) in women with grade 2 obesity (BMI >= 35 kg/m(2)) and a high WC (> 102/88 cm). Among the large group of overweight individuals, WC measurement was highly informative and facilitated the identification of a subgroup of overweight people with high WC whose 10-y T2D cumulative incidence (men, 70 per 1,000 person-years; women, 44 per 1,000 person-years) was comparable to that of the obese group (50-103 per 1,000 person-years in men and 28-74 per 1,000 person-years in women).

    Conclusions: WC is independently and strongly associated with T2D, particularly in women, and should be more widely measured for risk stratification. If targeted measurement is necessary for reasons of resource scarcity, measuring WC in overweight individuals may be an effective strategy, since it identifies a high-risk subgroup of individuals who could benefit from individualised preventive action.

  • 41.
    Lawson, Claire A.
    et al.
    Univ Leicester, England.
    Solis-Trapala, Ivonne
    Keele Univ, England.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Mamas, Mamas
    Keele Univ, England.
    Jaarsma, Tiny
    Linköping University, Department of Social and Welfare Studies, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Australian Catholic Univ, Australia.
    Kadam, Umesh T.
    Univ Leicester, England.
    Strömberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Comorbidity health pathways in heart failure patients: A sequences-of-regressions analysis using cross-sectional data from 10,575 patients in the Swedish Heart Failure Registry2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 3, article id e1002540Article in journal (Refereed)
    Abstract [en]

    Background amp; para;amp; para;Optimally treated heart failure (HF) patients often have persisting symptoms and poor health-related quality of life. Comorbidities are common, but little is known about their impact on these factors, and guideline-driven HF care remains focused on cardiovascular status. The following hypotheses were tested: (i) comorbidities are associated with more severe symptoms and functional limitations and subsequently worse patient-rated health in HF, and (ii) these patterns of association differ among selected comorbidities.amp; para;amp; para;Methods and findings amp; para;amp; para;The Swedish Heart Failure Registry (SHFR) is a national population-based register of HF patients admitted to amp;gt;85% of hospitals in Sweden or attending outpatient clinics. This study included 10,575 HF patients with patient-rated health recorded during first registration in the SHFR (1 February 2008 to 1 November 2013). An a priori health model and sequences-of-regressions analysis were used to test associations among comorbidities and patient-reported symptoms, functional limitations, and patient-rated health. Patient-rated health measures included the EuroQol-5 dimension (EQ-5D) questionnaire and the EuroQol visual analogue scale (EQ-VAS). EQ-VAS score ranges from 0 (worst health) to 100 (best health). Patient-rated health declined progressively from patients with no comorbidities (mean EQVAS score, 66) to patients with cardiovascular comorbidities (mean EQ-VAS score, 62) to patients with non-cardiovascular comorbidities (mean EQ-VAS score, 59). The relationships among cardiovascular comorbidities and patient-rated health were explained by their associations with anxiety or depression (atrial fibrillation, odds ratio [OR] 1.16, 95% CI 1.06 to 1.27; ischemic heart disease [IHD], OR 1.20, 95% CI 1.09 to 1.32) and with pain (IHD, OR 1.25, 95% CI 1.14 to 1.38). Associations of non-cardiovascular comorbidities with patient-rated health were explained by their associations with shortness of breath (diabetes, OR 1.17, 95% CI 1.03 to 1.32; chronic kidney disease [CKD, OR 1.23, 95% CI 1.10 to 1.38; chronic obstructive pulmonary disease [COPD], OR 95% CI 1.84, 1.62 to 2.10) and with fatigue (diabetes, OR 1.27, 95% CI 1.13 to 1.42; CKD, OR 1.24, 95% CI 1.12 to 1.38; COPD, OR 1.69, 95% CI 1.50 to 1.91). There were direct associations between all symptoms and patient-rated health, and indirect associations via functional limitations. Anxiety or depression had the strongest association with functional limitations (OR 10.03, 95% CI 5.16 to 19.50) and patient-rated health (mean difference in EQ-VAS score, -18.68, 95% CI -23.22 to -14.14). HF optimizing therapies did not influence these associations. Key limitations of the study include the cross-sectional design and unclear generalisability to other populations. Further prospective HF studies are required to test the consistency of the relationships and their implications for health.amp; para;amp; para;Conclusions amp; para;amp; para;Identification of distinct comorbidity health pathways in HF could provide the evidence for individualised person-centred care that targets specific comorbidities and associated symptoms.

  • 42.
    Lei, Jiayao
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Ploner, Alexander
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Lagheden, Camilla
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Eklund, Carina
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Kleppe, Sara Nordqvist
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Andrae, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Elfström, K. Miriam
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden;Reg Canc Ctr Stockholm Gotland, Stockholm, Sweden.
    Dillner, Joakim
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden;Karolinska Univ Hosp, Karolinska Univ Lab, Stockholm, Sweden.
    Sparén, Pär
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Sundström, Karin
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden;Karolinska Univ Hosp, Karolinska Univ Lab, Stockholm, Sweden.
    High-risk human papillomavirus status and prognosis in invasive cervical cancer: A nationwide cohort study2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 10, article id e1002666Article in journal (Refereed)
    Abstract [en]

    Background: High-risk human papillomavirus (hrHPV) infection is established as the major cause of invasive cervical cancer (ICC). However, whether hrHPV status in the tumor is associated with subsequent prognosis of ICC is controversial. We aim to evaluate the association between tumor hrHPV status and ICC prognosis using national registers and comprehensive human papillomavirus (HPV) genotyping.

    Methods and findings: In this nationwide population-based cohort study, we identified all ICC diagnosed in Sweden during the years 2002-2011 (4,254 confirmed cases), requested all archival formalin-fixed paraffin-embedded blocks, and performed HPV genotyping. Twenty out of 25 pathology bio-banks agreed to the study, yielding a total of 2,845 confirmed cases with valid HPV results. Cases were prospectively followed up from date of cancer diagnosis to 31 December 2015, migration from Sweden, or death, whichever occurred first. The main exposure was tumor hrHPV status classified as hrHPV-positive and hrHPV-negative. The primary outcome was all-cause mortality by 31 December 2015. Five-year relative survival ratios (RSRs) were calculated, and excess hazard ratios (EHRs) with 95% confidence intervals (CIs) were estimated using Poisson regression, adjusting for education, time since cancer diagnosis, and clinical factors including age at cancer diagnosis and International Federation of Gynecology and Obstetrics (FIGO) stage. Of the 2,845 included cases, hrHPV was detected in 2,293 (80.6%), and we observed 1,131 (39.8%) deaths during an average of 6.2 years follow-up. The majority of ICC cases were diagnosed at age 30-59 years (57.5%) and classified as stage IB (40.7%). hrHPV positivity was significantly associated with screen-detected tumors, young age, high education level, and early stage at diagnosis (p < 0.001). The 5-year RSR compared to the general female population was 0.74 (95% CI 0.72-0.76) for hrHPV-positive cases and 0.54 (95% CI 0.50-0.59) for hrHPV-negative cases, yielding a crude EHR of 0.45 (95% CI 0.38-0.52) and an adjusted EHR of 0.61 (95% CI 0.52-0.71). Risk of all-cause mortality as measured by EHR was consistently and statistically significantly lower for cases with hrHPV-positive tumors for each age group above 29 years and each FIGO stage above IA. The difference in prognosis by hrHPV status was highly robust, regardless of the clinical, histological, and educational characteristics of the cases. The main limitation was that, except for education, we were not able to adjust for lifestyle factors or other unmeasured confounders.

    Conclusions: In this study, women with hrHPV-positive cervical tumors had a substantially better prognosis than women with hrHPV-negative tumors. hrHPV appears to be a biomarker for better prognosis in cervical cancer independent of age, FIGO stage, and histological type, extending information from already established prognostic factors. The underlying biological mechanisms relating lack of detectable tumor hrHPV to considerably worse prognosis are not known and should be further investigated.

  • 43. Lindqvist, Olav
    et al.
    Tishelman, Carol
    Hagelin, Carina Lundh
    Karolinska institutet, Sophiahemmet högskola.
    Clark, Jean B
    Daud, Maria L
    Dickman, Andrew
    Benedetti, Franzisca Domeisen
    Galushko, Maren
    Lunder, Urska
    Lundquist, Gunilla
    Miccinesi, Guido
    Sauter, Sylvia B
    Fürst, Carl Johan
    Rasmussen, Birgit H
    Complexity in non-pharmacological caregiving activities at the end of life: an international qualitative study.2012In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 9, no 2, article id e1001173Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In late-stage palliative cancer care, relief of distress and optimized well-being become primary treatment goals. Great strides have been made in improving and researching pharmacological treatments for symptom relief; however, little systematic knowledge exists about the range of non-pharmacological caregiving activities (NPCAs) staff use in the last days of a patient's life.

    METHODS AND FINDINGS: Within a European Commission Seventh Framework Programme project to optimize research and clinical care in the last days of life for patients with cancer, OPCARE9, we used a free-listing technique to identify the variety of NPCAs performed in the last days of life. Palliative care staff at 16 units in nine countries listed in detail NPCAs they performed over several weeks. In total, 914 statements were analyzed in relation to (a) the character of the statement and (b) the recipient of the NPCA. A substantial portion of NPCAs addressed bodily care and contact with patients and family members, with refraining from bodily care also described as a purposeful caregiving activity. Several forms for communication were described; information and advice was at one end of a continuum, and communicating through nonverbal presence and bodily contact at the other. Rituals surrounding death and dying included not only spiritual/religious issues, but also more subtle existential, legal, and professional rituals. An unexpected and hitherto under-researched area of focus was on creating an aesthetic, safe, and pleasing environment, both at home and in institutional care settings.

    CONCLUSIONS: Based on these data, we argue that palliative care in the last days of life is multifaceted, with physical, psychological, social, spiritual, and existential care interwoven in caregiving activities. Providing for fundamental human needs close to death appears complex and sophisticated; it is necessary to better distinguish nuances in such caregiving to acknowledge, respect, and further develop end-of-life care.

  • 44.
    Lindqvist, Olav
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing.
    Tishelman, Carol
    Lundh Hagelin, Carina
    Clark, Jean B.
    Daud, Maria L.
    Dickman, Andrew
    Domeisen Benedetti, Franzisca
    Galushko, Maren
    Lunder, Urska
    Lundquist, Gunilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Miccinesi, Guido
    Sauter, Sylvia B.
    Fürst, Carl Johan
    Holritz Rasmussen, Birgit
    Umeå University, Faculty of Medicine, Department of Nursing.
    Complexity in Non-Pharmacological Caregiving Activities at the End of Life: An International Qualitative Study2012In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 9, no 2, p. e1001173-Article in journal (Refereed)
    Abstract [en]

    Background: In late-stage palliative cancer care, relief of distress and optimized well-being become primary treatment goals. Great strides have been made in improving and researching pharmacological treatments for symptom relief; however, little systematic knowledge exists about the range of non-pharmacological caregiving activities (NPCAs) staff use in the last days of a patient's life. Methods and Findings: Within a European Commission Seventh Framework Programme project to optimize research and clinical care in the last days of life for patients with cancer, OPCARE9, we used a free-listing technique to identify the variety of NPCAs performed in the last days of life. Palliative care staff at 16 units in nine countries listed in detail NPCAs they performed over several weeks. In total, 914 statements were analyzed in relation to (a) the character of the statement and (b) the recipient of the NPCA. A substantial portion of NPCAs addressed bodily care and contact with patients and family members, with refraining from bodily care also described as a purposeful caregiving activity. Several forms for communication were described; information and advice was at one end of a continuum, and communicating through nonverbal presence and bodily contact at the other. Rituals surrounding death and dying included not only spiritual/religious issues, but also more subtle existential, legal, and professional rituals. An unexpected and hitherto under-researched area of focus was on creating an aesthetic, safe, and pleasing environment, both at home and in institutional care settings. Conclusions: Based on these data, we argue that palliative care in the last days of life is multifaceted, with physical, psychological, social, spiritual, and existential care interwoven in caregiving activities. Providing for fundamental human needs close to death appears complex and sophisticated; it is necessary to better distinguish nuances in such caregiving to acknowledge, respect, and further develop end-of-life care.

  • 45. Lindqvist, Olav
    et al.
    Tishelman, Carol
    Lundh Hagelin, Carina
    Sophiahemmet University.
    Clark, Jean B
    Daud, Maria L
    Dickman, Andrew
    Domeisen Benedetti, Franzisca
    Galushko, Maren
    Lunder, Urska
    Lundquist, Gunilla
    Miccinesi, Guido
    Sauter, Sylvia B
    Fürst, Carl Johan
    Rasmussen, Birgit H
    Complexity in non-pharmacological care-giving activities at the end of life: an international qualitative study2012In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 9, no 2, p. 1-10Article in journal (Refereed)
  • 46.
    Low, Nicola
    et al.
    Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
    Unemo, Magnus
    Örebro University Hospital. World Health Org Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, Örebro University Hospital, Örebro, Sweden.
    Jensen, Jorgen Skov
    Dept Microbiol & Infect Control, Statens Serum Inst, Copenhagen, Denmark.
    Breuer, Judith
    Div Infect & Immun, Medical Research Council (MRC) UCL Ctr Med Mol Virol, University College London, London, England.
    Stephenson, Judith M.
    Inst Womens Hlth, University College London, London, England.
    Molecular Diagnostics for Gonorrhoea: Implications for Antimicrobial Resistance and the Threat of Untreatable Gonorrhoea2014In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 11, no 2, article id e1001598Article in journal (Refereed)
  • 47.
    Ludvigsson, Jonas F.
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Orebro Univ Hosp, Dept Pediat, Orebro, Sweden.;Univ Nottingham, Div Epidemiol & Publ Hlth, Sch Med, Nottingham, England.;Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA..
    Lu, Donghao
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Univ Iceland, Fac Med, Ctr Publ Hlth Sci, Reykjavik, Iceland..
    Hammarstrom, Lennart
    Karolinska Inst, Dept Lab Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Cnattingius, Sven
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Fang, Fang
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Small for gestational age and risk of childhood mortality: A Swedish population study2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 12, article id e1002717Article in journal (Refereed)
    Abstract [en]

    Background: Small for gestational age (SGA) has been associated with increased risks of stillbirth and neonatal mortality, but data on long-term childhood mortality are scarce. Maternal antenatal care, including globally reducing the risk of SGA birth, may be key to achieving the Millennium Development Goal of reducing under-5 mortality. We therefore aimed to examine the association between SGA and mortality from 28 days to <18 years using a population-based and a sibling control design.

    Methods and findings: In a Swedish population study, we identified 3,795,603 non-malformed singleton live births and 2,781,464 full siblings born from January 1, 1973, to December 31, 2012. We examined the associations of severe (<3rd percentile) and moderate (3rd to <10th percentile) SGA with risks of death from 28 days to <18 years after birth. Children born SGA were first compared to non-SGA children from the population, and then to non-SGA siblings. The sibling-based analysis, by design, features a better control for unmeasured factors that are shared between siblings (e.g., socioeconomic status, lifestyle, and genetic factors). Hazard ratios (HRs) were calculated using Cox proportional hazards and flexible parametric survival models. During follow-up (1973-2013), there were 10,838 deaths in the population-based analysis and 1,572 deaths in sibling pairs with discordant SGA and mortality status. The crude mortality rate per 10,000 person-years was 5.32 in children born with severe SGA, 2.76 in children born with moderate SGA, and 1.93 in non-SGA children. Compared with non-SGA children, children born with severe SGA had an increased risk of death in both the population-based (HR = 2.58, 95% CI = 2.38-2.80) and sibling-based (HR = 2.61, 95% CI = 2.19-3.10) analyses. Similar but weaker associations were found for moderate SGA in the population-based (HR = 1.37, 95% CI = 1.28-1.47) and sibling-based (HR = 1.38, 95% CI = 1.22-1.56) analyses. The excess risk was most pronounced between 28 days and <1 year of age but remained throughout childhood. The greatest risk increase associated with severe SGA was noted for deaths due to infection and neurologic disease. Although we have, to our knowledge, the largest study sample so far addressing the research question, some subgroup analyses, especially the analysis of cause-specific mortality, had limited statistical power using the sibling-based approach.

    Conclusions: We found that SGA, especially severe SGA, was associated with an increased risk of childhood death beyond the neonatal period, with the highest risk estimates for death from infection and neurologic disease. The similar results obtained between the population- and sibling-based analyses argue against strong confounding by factors shared within families.

  • 48.
    Mackenbach, Johan P
    et al.
    Erasmus University Medical Center, Rotterdam, The Netherlands.
    Kulhánová, Ivana
    Erasmus University Medical Center, Rotterdam, The Netherlands.
    Bopp, Matthias
    University of Zurich, Zurich, Switzerland.
    Borrell, Carme
    Agència de Salut Pública de Barcelona, Barcelona, Spain.
    Deboosere, Patrick
    Vrije Universiteit Brussel, Brussels, Belgium.
    Kovács, Katalin
    Hungarian Central Statistical Office, Budapest, Hungary.
    Looman, Caspar W N
    Erasmus University Medical Center, Rotterdam, The Netherlands.
    Leinsalu, Mall
    Södertörn University, School of Social Sciences, Sociology. Södertörn University, School of Social Sciences, SCOHOST (Stockholm Centre for Health and Social Change). National Institute for Health Development, Tallinn, Estonia.
    Mäkelä, Pia
    National Institute for Health and Welfare, Helsinki, Finland.
    Martikainen, Pekka
    University of Helsinki, Helsinki, Finland.
    Menvielle, Gwenn
    Sorbonne Universités, Paris, France.
    Rodríguez-Sanz, Maica
    Agència de Salut Pública de Barcelona, Barcelona, Spain.
    Rychtaříková, Jitka
    Charles University, Prague, Czech Republic.
    de Gelder, Rianne
    Erasmus University Medical Center, Rotterdam, The Netherlands.
    Inequalities in Alcohol-Related Mortality in 17 European Countries: A Retrospective Analysis of Mortality Registers.2015In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 12, no 12, article id e1001909Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Socioeconomic inequalities in alcohol-related mortality have been documented in several European countries, but it is unknown whether the magnitude of these inequalities differs between countries and whether these inequalities increase or decrease over time.

    METHODS AND FINDINGS: We collected and harmonized data on mortality from four alcohol-related causes (alcoholic psychosis, dependence, and abuse; alcoholic cardiomyopathy; alcoholic liver cirrhosis; and accidental poisoning by alcohol) by age, sex, education level, and occupational class in 20 European populations from 17 different countries, both for a recent period and for previous points in time, using data from mortality registers. Mortality was age-standardized using the European Standard Population, and measures for both relative and absolute inequality between low and high socioeconomic groups (as measured by educational level and occupational class) were calculated. Rates of alcohol-related mortality are higher in lower educational and occupational groups in all countries. Both relative and absolute inequalities are largest in Eastern Europe, and Finland and Denmark also have very large absolute inequalities in alcohol-related mortality. For example, for educational inequality among Finnish men, the relative index of inequality is 3.6 (95% CI 3.3-4.0) and the slope index of inequality is 112.5 (95% CI 106.2-118.8) deaths per 100,000 person-years. Over time, the relative inequality in alcohol-related mortality has increased in many countries, but the main change is a strong rise of absolute inequality in several countries in Eastern Europe (Hungary, Lithuania, Estonia) and Northern Europe (Finland, Denmark) because of a rapid rise in alcohol-related mortality in lower socioeconomic groups. In some of these countries, alcohol-related causes now account for 10% or more of the socioeconomic inequality in total mortality. Because our study relies on routinely collected underlying causes of death, it is likely that our results underestimate the true extent of the problem.

    CONCLUSIONS: Alcohol-related conditions play an important role in generating inequalities in total mortality in many European countries. Countering increases in alcohol-related mortality in lower socioeconomic groups is essential for reducing inequalities in mortality. Studies of why such increases have not occurred in countries like France, Switzerland, Spain, and Italy can help in developing evidence-based policies in other European countries.

  • 49.
    Mascalzoni, Deborah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Hicks, Andrew
    Pramstaller, Peter
    Wjst, Matthias
    Informed consent in the genomics era.2008In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 5, no 9, p. e192-194Article in journal (Refereed)
  • 50.
    Mendelson, Michael M.
    et al.
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;Boston Univ, Sch Med, Boston, MA 02118 USA.;Boston Childrens Hosp, Dept Cardiol, Boston, MA USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Marioni, Riccardo E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Joehanes, Roby
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA.;Harvard Med Sch, Hebrew SeniorLife, Boston, MA USA..
    Liu, Chunyu
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA.;Boston Univ, Dept Biostat, Boston, MA USA..
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Aslibekyan, Stella
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Demerath, Ellen W.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    Guan, Weihua
    Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA..
    Zhi, Degui
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA..
    Yao, Chen
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Huan, Tianxiao
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Willinger, Christine
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Chen, Brian
    NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Courchesne, Paul
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Multhaup, Michael
    Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD USA..
    Lrvin, Marguerite R.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Cohain, Ariella
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Schadt, Eric E.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Grove, Megan L.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA..
    Bressler, Jan
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA..
    North, Kari
    Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Shah, Sonia
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    McRae, Allan F.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Harris, Sarah E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH8 9YL, Midlothian, Scotland..
    Gibson, Jude
    Univ Edinburgh, Western Gen Hosp, Wellcome Trust Clin Res Facil, Edinburgh EH8 9YL, Midlothian, Scotland..
    Redmond, Paul
    Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland..
    Coriey, Janie
    Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland..
    Murphy, Lee
    Univ Edinburgh, Western Gen Hosp, Wellcome Trust Clin Res Facil, Edinburgh EH8 9YL, Midlothian, Scotland..
    Starr, John M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland..
    Kleinbrink, Erica
    Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA.;Wayne State Univ, Dept Neurol, Detroit, MI USA..
    Lipovich, Leonard
    Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA.;Wayne State Univ, Dept Neurol, Detroit, MI USA..
    Visscher, Peter M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Wray, Naomi R.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Krauss, Ronald M.
    Childrens Hosp Oakland Res Inst, Oakland, CA USA..
    Fallin, Daniele
    Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD USA..
    Feinberg, Andrew
    Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD USA..
    Absher, Devin M.
    HudsonAlpha Inst Biotechnol, Huntsville, AL USA..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Univ Texas Houston, Brown Fdn Inst Mol Med, Houston, TX USA..
    Pankow, James S.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fox, Caroline
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Arnett, Donna K.
    Univ Kentucky, Coll Publ Hlth, Lexington, KY USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Liang, Liming
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA..
    Levy, Daniel
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Deary, Lan J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland..
    Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 1, article id e1002215Article in journal (Refereed)
    Abstract [en]

    Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.

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