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  • 1.
    Abujrais, Sandy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ahnoff, Martin
    Department of Marine Sciences, University of Gothenburg, Carl Skottbergs gata 22B, SE-41319 Gothenburg, Sweden..
    Rasmusson, Annica J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Åkerfeldt, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    A sensitive method detecting trace levels of levonorgestrel using LC-HRMS.2019In: Contraception, ISSN 0010-7824, E-ISSN 1879-0518, article id S0010-7824(19)30200-8Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To develop a high resolution mass spectrometry (HRMS) method to quantify levonorgestrel (LNG) in serum.

    STUDY DESIGN: Levonorgestrel was extracted using solid phase extraction and measured using liquid chromatography (LC) HRMS.

    RESULTS: Low limit of quantification (LLOQ) was 25pg/mL and low limit of detection (LLOD) was 12.5pg/mL. Precision and accuracy bias were<10%. LNG in serum samples from Mirena® users ranged between 37 to 219pg/mL (n=12). In eight out of 22 patients with suspected intrauterine device (IUD) expulsion LNG was detected (26 to 1272pg/mL).

    CONCLUSION: A sensitive, fast and simple LC-HRMS method was developed to detect trace levels of LNG.

  • 2.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Naessen, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sub-clinical atherosclerosis in the common carotid artery in women with/without previous pre-eclampsia: A seven-year follow-up.2019In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, article id S0021-9150(19)30449-6Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Pre-eclampsia is associated with increased risk of cardiovascular disease and premature death. However, conventional common carotid artery intima-media thickness (CCA-IMT) measurement does not reflect this. In contrast, measurement of the individual CCA intima and media thicknesses clearly indicates increased vascular risk both at diagnosis and about one year after pre-eclampsia. This study examined whether individual CCA wall layers, risk factors for cardiovascular disease, and markers of endothelial dysfunction had normalized or remained unfavorable seven years after pre-eclampsia.

    METHODS: The individual CCA intima and media thicknesses were measured using 22 MHz ultrasound. Conventional cardiovascular risk factors were recorded. A thick intima, thin media and high intima/media thickness ratio (I/M) are signs of sub-clinical atherosclerosis.

    RESULTS: The median age of women with previous pre-eclampsia (cases = 23) or normal pregnancies (controls = 35) was 39/37 years. At follow-up (median about seven years), the intima remained thicker and the I/M was higher in cases than in controls [all p < 0.0001; p < 0.001 after adjustment for time to follow-up, body mass index (BMI), and mean arterial pressure (MAP)], whereas the CCA-IMT was illogically thinner. Further, BMI, MAP, hip circumference, abdominal height, serum endostatin and apolipoprotein B levels were higher in cases (all p < 0.05). Intima and I/M measurements were correlated with age, MAP, endostatin and apolipoprotein B, whereas no logical correlations were found for CCA-IMT.

    CONCLUSIONS: The arteries in cases but not controls were still adversely affected after seven years. Measuring intima thickness and I/M appears preferable to measuring CCA-IMT for demonstrating vascular risk after pre-eclampsia.

  • 3.
    Akhter, Tansim
    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), Gynecological endocrinology.
    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, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Larsson, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Naessén, Tord
    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), Gynecological endocrinology.
    Serum Pentraxin 3 is associated with signs of arterial alteration in women with preeclampsia.2017In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 241, p. 417-422Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Preeclampsia (PE) in pregnancy is a state of exaggerated inflammation and is associated with an increased risk of cardiovascular disease (CVD) later in life. Levels of pentraxin 3 (PTX3), a novel inflammation marker, are increased during PE and in individuals with CVD. The primary aim of this study was to assess whether serum PTX3 in women with PE is associated with adverse arterial effects; a thicker intima and higher intima/media (I/M) ratio in the common carotid artery (CCA).

    METHODS: Serum PTX3 levels were measured using commercially available enzyme-linked immunosorbent assay kits, and individual CCA intima and media thicknesses were estimated by 22MHz non-invasive ultrasound in 55 women at PE diagnosis and 64 women with normal pregnancies at a similar gestational age, and about one year postpartum. A thick intima, thin media and high I/M ratio indicate a less healthy artery wall.

    RESULTS: During pregnancy serum PTX3 correlated positively with intima thickness and I/M ratio but negatively with media thickness (all p<0.0001), indicating adverse arterial effects. About one year postpartum, PTX3 levels had decreased in both groups and there remained no significant group difference or significant correlation with CCA wall layers.

    CONCLUSIONS: Higher levels of serum PTX3 in women with PE were significantly associated with signs of adverse arterial effects during pregnancy, but not one year postpartum, supporting the rapid dynamics of PTX3.

  • 4. Alehagen, Urban
    et al.
    Aaseth, Jan
    Alexander, Jan
    Svensson, Erland
    Johansson, Peter
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Less fibrosis in elderly subjects supplemented with selenium and coenzyme Q10-A mechanism behind reduced cardiovascular mortality?2018In: Biofactors, ISSN 0951-6433, E-ISSN 1872-8081, Vol. 44, no 2, p. 137-147Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In an intervention study where 221 healthy elderly persons received selenium and coenzyme Q10 as a dietary supplement, and 222 received placebo for 4 years we observed improved cardiac function and reduced cardiovascular mortality. As fibrosis is central in the aging process, we investigated the effect of the intervention on biomarkers of fibrogenic activity in a subanalysis of this intervention study.

    MATERIAL AND METHODS: In the present subanalysis 122 actively treated individuals and 101 controls, the effect of the treatment on eight biomarkers of fibrogenic activity were assessed. These biomarkers were: Cathepsin S, Endostatin, Galectin 3, Growth Differentiation Factor-15 (GDF-15), Matrix Metalloproteinases 1 and 9, Tissue Inhibitor of Metalloproteinases 1 (TIMP 1) and Suppression of Tumorigenicity 2 (ST-2). Blood concentrations of these biomarkers after 6 and 42 months were analyzed by the use of T-tests, repeated measures of variance, and factor analyses.

    RESULTS: Compared with placebo, in those receiving supplementation with selenium and coenzyme Q10, all biomarkers except ST2 showed significant decreased concentrations in blood. The changes in concentrations, that is, effects sizes as given by partial eta2 caused by the intervention were considered small to medium.

    CONCLUSION: The significantly decreased biomarker concentrations in those on active treatment with selenium and coenzyme Q10 compared with those on placebo after 36 months of intervention presumably reflect less fibrogenic activity as a result of the intervention. These observations might indicate that reduced fibrosis precedes the reported improvement in cardiac function, thereby explaining some of the positive clinical effects caused by the intervention. © 2017 BioFactors, 2017.

  • 5.
    Alehagen, Urban
    et al.
    Linkoping Univ, Dept Med & Hlth Sci, Div Cardiovasc Med, SE-58185 Linkoping, Sweden.
    Alexander, Jan
    Norwegian Inst Publ Hlth, N-0403 Oslo, Norway.
    Aaseth, Jan
    Innlandet Hosp Trust, Res Dept, Brumunddal, Norway;Inland Norway Univ Appl Sci, N-2411 Elverum, Norway.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Decrease in inflammatory biomarker concentration by intervention with selenium and coenzyme Q10: a subanalysis of osteopontin, osteoprotergerin, TNFr1, TNFr2 and TWEAK2019In: Journal of Inflammation, ISSN 1476-9255, E-ISSN 1476-9255, Vol. 16, article id 5Article in journal (Refereed)
    Abstract [en]

    Background:

    Inflammation is central to the pathogenesis of many diseases. Supplementation with selenium and coenzyme Q10 has been shown to reduce cardiovascular mortality, and increase cardiac function in elderly persons with a low intake of selenium. There are indications that one of the mechanisms of this positive effect is a decrease in inflammation.

    Methods:

    Osteopontin, osteoprotegerin, sTNF receptor 1, sTNF receptor 2 and the tumor necrosis factor-like weak inducer of apoptosis called TWEAK, were determined in plasma after 6 months and 42months in 219 community-living elderly persons, of whom 119 received supplements of selenium (200g/day) and coenzyme Q10 (200mg/day), and 101 received a placebo. Repeated measures of variance were used to evaluate the levels, and the results were validated through ANCOVA analyses with adjustments for important covariates.

    Results:

    Significantly lower concentrations of four of the five biomarkers for inflammation were observed as a result of the intervention with the supplements. Only TWEAK did not show significant differences.

    Conclusion:

    In this sub-analysis of the intervention with selenium and coenzyme Q10 or placebo in an elderly community-living population, biomarkers for inflammation were evaluated. A significantly lower concentration in four of the five biomarkers tested could be demonstrated as a result of the supplementation, indicating a robust effect on the inflammatory system. The decrease in inflammation could be one of the mechanisms behind the positive clinical results on reduced cardiovascular morbidity and mortality reported earlier as a result of the intervention. The study is small and should be regarded as hypothesis-generating, but nonetheless adds important data about mechanisms presently known to increase the risk of clinical effects such as reduced cardiovascular mortality, increased cardiac function and better health-related quality of life scoring, as previously demonstrated in the active treatment group.

  • 6.
    Alehagen, Urban
    et al.
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, SE-581 85 Linköping, Sweden..
    Alexander, Jan
    Norwegian Institute of Public Health, N-0403 Oslo, Norway..
    Aaseth, Jan
    Inland Norway University of Applied Sciences, N-2411 Elverum, Norway..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Decrease in inflammatory biomarker concentration by intervention with selenium and coenzyme Q10: a subanalysis of osteopontin, osteoprotergerin, TNFr1, TNFr2 and TWEAK.2019In: Journal of Inflammation, ISSN 1476-9255, E-ISSN 1476-9255, Vol. 16, article id 5Article in journal (Refereed)
    Abstract [en]

    Background: Inflammation is central to the pathogenesis of many diseases. Supplementation with selenium and coenzyme Q10 has been shown to reduce cardiovascular mortality, and increase cardiac function in elderly persons with a low intake of selenium. There are indications that one of the mechanisms of this positive effect is a decrease in inflammation.

    Methods: Osteopontin, osteoprotegerin, sTNF receptor 1, sTNF receptor 2 and the tumor necrosis factor-like weak inducer of apoptosis called TWEAK, were determined in plasma after 6 months and 42 months in 219 community-living elderly persons, of whom 119 received supplements of selenium (200 μg/day) and coenzyme Q10 (200 mg/day), and 101 received a placebo. Repeated measures of variance were used to evaluate the levels, and the results were validated through ANCOVA analyses with adjustments for important covariates.

    Results: Significantly lower concentrations of four of the five biomarkers for inflammation were observed as a result of the intervention with the supplements. Only TWEAK did not show significant differences.

    Conclusion: In this sub-analysis of the intervention with selenium and coenzyme Q10 or placebo in an elderly community-living population, biomarkers for inflammation were evaluated. A significantly lower concentration in four of the five biomarkers tested could be demonstrated as a result of the supplementation, indicating a robust effect on the inflammatory system. The decrease in inflammation could be one of the mechanisms behind the positive clinical results on reduced cardiovascular morbidity and mortality reported earlier as a result of the intervention. The study is small and should be regarded as hypothesis-generating, but nonetheless adds important data about mechanisms presently known to increase the risk of clinical effects such as reduced cardiovascular mortality, increased cardiac function and better health-related quality of life scoring, as previously demonstrated in the active treatment group .

    Trial registration: The intervention study was registered at Clinicaltrials.gov, and has the identifier NCT01443780 and registered on 09/30/2011.

  • 7. Barber, RM
    et al.
    Fullman, N
    Sorensen, RJD
    Bollyky, T
    McKee, M
    Nolte, E
    Abajobir, AA
    Abate, KH
    Abbafati, C
    Abbas, KM
    Abd-Allah, F
    Abdulle, AM
    Ärnlöv, Johan
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Younis, MZ
    Yu, C
    Zaidi, Z
    El Sayed Zaki, M
    Zambrana-Torrelio, C
    Zapata, T
    Zenebe, ZM
    Zodpey, S
    Zoeckler, L
    Zuhlke, LJ
    Murray, CJL
    Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990-2015: a novel analysis from the Global Burden of Disease Study 2015.2017In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 390, no 10091, p. 231-266Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015.

    METHODS: We mapped the most widely used list of causes amenable to personal health care developed by Nolte and McKee to 32 GBD causes. We accounted for variations in cause of death certification and misclassifications through the extensive data standardisation processes and redistribution algorithms developed for GBD. To isolate the effects of personal health-care access and quality, we risk-standardised cause-specific mortality rates for each geography-year by removing the joint effects of local environmental and behavioural risks, and adding back the global levels of risk exposure as estimated for GBD 2015. We employed principal component analysis to create a single, interpretable summary measure-the Healthcare Quality and Access (HAQ) Index-on a scale of 0 to 100. The HAQ Index showed strong convergence validity as compared with other health-system indicators, including health expenditure per capita (r=0·88), an index of 11 universal health coverage interventions (r=0·83), and human resources for health per 1000 (r=0·77). We used free disposal hull analysis with bootstrapping to produce a frontier based on the relationship between the HAQ Index and the Socio-demographic Index (SDI), a measure of overall development consisting of income per capita, average years of education, and total fertility rates. This frontier allowed us to better quantify the maximum levels of personal health-care access and quality achieved across the development spectrum, and pinpoint geographies where gaps between observed and potential levels have narrowed or widened over time.

    FINDINGS: Between 1990 and 2015, nearly all countries and territories saw their HAQ Index values improve; nonetheless, the difference between the highest and lowest observed HAQ Index was larger in 2015 than in 1990, ranging from 28·6 to 94·6. Of 195 geographies, 167 had statistically significant increases in HAQ Index levels since 1990, with South Korea, Turkey, Peru, China, and the Maldives recording among the largest gains by 2015. Performance on the HAQ Index and individual causes showed distinct patterns by region and level of development, yet substantial heterogeneities emerged for several causes, including cancers in highest-SDI countries; chronic kidney disease, diabetes, diarrhoeal diseases, and lower respiratory infections among middle-SDI countries; and measles and tetanus among lowest-SDI countries. While the global HAQ Index average rose from 40·7 (95% uncertainty interval, 39·0-42·8) in 1990 to 53·7 (52·2-55·4) in 2015, far less progress occurred in narrowing the gap between observed HAQ Index values and maximum levels achieved; at the global level, the difference between the observed and frontier HAQ Index only decreased from 21·2 in 1990 to 20·1 in 2015. If every country and territory had achieved the highest observed HAQ Index by their corresponding level of SDI, the global average would have been 73·8 in 2015. Several countries, particularly in eastern and western sub-Saharan Africa, reached HAQ Index values similar to or beyond their development levels, whereas others, namely in southern sub-Saharan Africa, the Middle East, and south Asia, lagged behind what geographies of similar development attained between 1990 and 2015.

    INTERPRETATION: This novel extension of the GBD Study shows the untapped potential for personal health-care access and quality improvement across the development spectrum. Amid substantive advances in personal health care at the national level, heterogeneous patterns for individual causes in given countries or territories suggest that few places have consistently achieved optimal health-care access and quality across health-system functions and therapeutic areas. This is especially evident in middle-SDI countries, many of which have recently undergone or are currently experiencing epidemiological transitions. The HAQ Index, if paired with other measures of health-system characteristics such as intervention coverage, could provide a robust avenue for tracking progress on universal health coverage and identifying local priorities for strengthening personal health-care quality and access throughout the world.

    FUNDING: Bill & Melinda Gates Foundation.

  • 8.
    Basu, Samar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Univ Clermont Auvergne, Fac Pharm, Dept Biochem Mol Biol & Nutr, BP 10448, F-63000 Clermont Ferrand, France..
    Kadiiska, Maria B.
    NIEHS, Immun Inflammat & Dis Lab, NIH, Res Triangle Pk, NC 27709 USA..
    Ozone exposure effect on systemic prostaglandin F-2 alpha in rat plasma and urine may not reveal pulmonary damage through inflammation2017In: Prostaglandins, Leukotrienes and Essential Fatty Acids, ISSN 0952-3278, E-ISSN 1532-2823, Vol. 126, p. 79-83Article in journal (Refereed)
    Abstract [en]

    The acute ozone induced lung injury model has been widely used to explore injury and repair processes induced by oxidant overload. The current study evaluated acute ozone exposure effects on prostaglandin F-2 alpha (PGF(2 alpha)) in male Fischer rat plasma and urine with the hypothesis that ozone may induce an inflammatory response in the body that can be measured by the induction of PGF2 alpha. That might then lead to the identification of potential marker for acute lung injury through systemic inflammation. The time and dose-dependent effects of ozone exposure on the plasma and urinary levels of a major PGF(2 alpha) metabolite15-keto-dihydro-PGF(2 alpha) were determined using a radioimmunoassay. No statistically significant differences in the PGF(2 alpha) metabolite were found between the control and the experimental groups at either ozone exposure dose (2 ppm and 5 ppm) or any time point (2 h, 7 h and 16 h) post exposure for plasma and at 7 different post exposure time points (between 2 and 80 h) for urine. It is concluded that acute ozone exposure does not cause changes in plasma and urinary PGF(2 alpha), and therefore their measurement in plasma and urine may not be used to reveal pulmonary inflammation and damage by ozone.

  • 9.
    Bergman, Daniel
    et al.
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hansson-Hamlin, Helene
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Ström Holst, Bodil
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Investigation of interference from canine anti-mouse antibodies in hormone immunoassays.2019In: Veterinary clinical pathology, ISSN 0275-6382, E-ISSN 1939-165XArticle in journal (Refereed)
    Abstract [en]

    BACKGROUND: Canine anti-mouse antibodies are a potential source of immunoassay interference, but erroneous immunoassay results are not always easily identifiable. Anti-Müllerian hormone (AMH) is a marker for the presence of gonads in dogs, but elevated AMH concentrations in neutered dogs could also be caused by antibody interference. For other assays, a discrepant result obtained after antibody precipitation might indicate antibody interference.

    OBJECTIVES: We aimed to evaluate if canine anti-mouse antibodies are a source of erroneous results in the AMH assay and if antibody precipitation with polyethylene glycol (PEG) is a useful tool for detecting antibody interference in a variety of immunoassays used in the veterinary clinical laboratory.

    METHODS: Twenty-nine positive and 25 negative samples for anti-mouse antibodies were analyzed for AMH, canine total thyroxine (TT4 ), canine thyroid-stimulating hormone (TSH) and progesterone before and after treatment with PEG. Results that differed by more than four SDs from the intra-assay coefficients of variation were considered discrepant. Elevated AMH concentrations in neutered dogs with anti-mouse antibodies and no visible gonads present were considered evidence of interference.

    RESULTS: Evidence of antibody interference was found in two samples analyzed for AMH. The presence of anti-mouse antibodies did not lead to a higher proportion of discrepant results after PEG treatment for any of the immunoassays. The overall incidence of discrepant results for healthy controls was very high (73%).

    CONCLUSIONS: Canine anti-mouse antibodies are a source of erroneous AMH results. Antibody precipitation with PEG is not a useful tool for detecting interference caused by such antibodies.

  • 10.
    Bergman, Daniel
    et al.
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hansson-Hamlin, Helene
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Svensson, Anna
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Holst, Bodil Ström
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Prevalence of interfering antibodies in dogs and cats evaluated using a species-independent assay.2018In: Veterinary clinical pathology, ISSN 0275-6382, E-ISSN 1939-165X, Vol. 47, no 2, p. 205-212Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Interfering antibodies in human serum and plasma are known to react with mammalian antibodies in immunoassays and cause false-positive test results. Although this phenomenon was recently shown in companion animals, knowledge regarding immunoassay interference in veterinary medicine is very limited.

    OBJECTIVES: The aims of this study were to set up a species-independent immunoassay procedure to detect interference in serum samples, to screen for interference in a cross-section of canine and feline patient samples from an animal hospital, and to determine if the detected interference could be neutralized using an immunoassay based on nonmammalian reagents.

    METHODS: A 2-site sandwich-type interference assay was set up using commercially available mouse reagents. A total of 369 serum samples from 320 dogs and 263 samples from 218 cats were analyzed using the interference assay. Multiple samples were submitted from 36 dogs and 39 cats. Nineteen samples identified as interference-positive were analyzed in an assay using chicken antibodies.

    RESULTS: Interference was detected in samples from 28 dogs (9%) and 10 cats (5%) screened with the interference assay. Except for 1 cat, consistent results were obtained for all 75 dogs and cats that submitted more than 1 sample. The interference was eliminated when analyzed in the chicken-based assay (P < .001).

    CONCLUSIONS: Substances with reactivity toward mouse IgG can be detected in serum samples from dog and cat patients using a 2-site interference assay. The detected substances are most likely interfering antibodies, possibly originating from immunization with other mammalian species.

  • 11.
    Bergqvist, Filip
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Ossipova, Elena
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Idborg, Helena
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Raouf, Joan
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Checa, Antonio
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden.
    Englund, Karin
    Stockholm Univ, Dept Analyt Chem, Stockholm, Sweden.
    Englund, Petter
    Stockholm Univ, Dept Analyt Chem, Stockholm, Sweden.
    Emami Khoonsari, Payam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wheelock, Craig E.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden.
    Larsson, Karin
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Korotkova, Marina
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Jakobsson, Per-Johan
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 636Article in journal (Refereed)
    Abstract [en]

    Pharmacological inhibition of microsomal prostaglandin E synthase (mPGES)-1 for selective reduction in prostaglandin E-2 (PGE(2)) biosynthesis is protective in experimental models of cancer and inflammation. Targeting mPGES-1 is envisioned as a safer alternative to traditional non-steroidal anti-inflammatory drugs (NSAIDs). Herein, we compared the effects of mPGES-1 inhibitor Compound III (CIII) with the cyclooxygenase (COX)-2 inhibitor NS-398 on protein and lipid profiles in interleukin (IL)-1 beta-induced A549 lung cancer cells using mass spectrometry. Inhibition of mPGES-1 decreased PGE(2) production and increased PGF(2 alpha) and thromboxane B-2 (TXB2) formation, while inhibition of COX-2 decreased the production of all three prostanoids. Our proteomics results revealed that CIII downregulated multiple canonical pathways including eIF2, eIF4/P70S6K, and mTOR signaling, compared to NS-398 that activated these pathways. Moreover, pathway analysis predicted that CIII increased cell death of cancer cells (Z = 3.8, p = 5.1E-41) while NS-398 decreased the same function (Z = -5.0, p = 6.5E-35). In our lipidomics analyses, we found alterations in nine phospholipids between the two inhibitors, with a stronger alteration in the lysophospholipid (LPC) profile with NS-398 compared to CIII. Inhibition of mPGES-1 increased the concentration of sphinganine and dihydroceramide (C16:0D hCer), while inhibition of COX-2 caused a general decrease in most ceramides, again suggesting different effects on cell death between the two inhibitors. We showed that CIII decreased proliferation and potentiated the cytotoxic effect of the cytostatic drugs cisplatin, etoposide, and vincristine when investigated in a live cell imaging system. Our results demonstrate differences in protein and lipid profiles after inhibition of mPGES-1 or COX-2 with important implications on the therapeutic potential of mPGES-1 inhibitors as adjuvant treatment in cancer. We encourage further investigations to illuminate the clinical benefit of mPGES-1 inhibitors in cancer.

  • 12.
    Blom, Kristin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    ElShafie, Amir Ibrahim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Alribat Univ Hosp, Dept Clin Pathol & Microbiol, Khartoum, Sudan.
    Jönsson, Ulla-Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The genetically determined production of the alarmin eosinophil-derived neurotoxin is reduced in visceral leishmaniasis2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 1, p. 85-91Article in journal (Refereed)
    Abstract [en]

    Visceral leishmaniasis (VL) is the most severe form of leishmaniasis. Recent findings indicate that dendritic cells have a key role in the defense against the Leishmania parasite and that the activity of this cell may be modified by the eosinophil secretory protein eosinophil-derived neurotoxin (EDN). We hypothesized that the interactions between dendritic cells and EDN might be of importance in the disease development. Cellular content of EDN was analyzed by ELISA. The single-nucleotide polymorphisms at positions 405, 416, and 1122 in the EDN gene were analyzed by real-time PCR with TaqMan((R)) reagents. The study cohorts comprised 239 Sudanese subjects (65 healthy controls and 174 with VL) and 300 healthy Swedish controls. The eosinophil content of EDN was lower in VL as compared with controls (p < 0.0001). The EDN405 (G>C) genotype distribution was similar among Swedish and Sudanese controls, whereas VL subjects had a higher prevalence of the EDN405-GG genotype (p < 0.0001). The content of EDN in the eosinophils was closely linked to the EDN405 polymorphism (p = 0.0002). Our findings suggest that the predisposition to acquire VL is related to the genetic polymorphism of the EDN gene and the reduced production by the eosinophil of this gene product.

  • 13. Bäckryd, Emmanuel
    et al.
    Lind, Anne-Li
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Berzelii Technology Center for Neurodiagnostics, Uppsala University, Uppsala, Sweden.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Gerdle, Björn
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Berzelii Technology Center for Neurodiagnostics, Uppsala University, Uppsala, Sweden.
    High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls2017In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, no 12, p. 2487-2495Article in journal (Refereed)
    Abstract [en]

    Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called "gliotransmitters," a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n = 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.

  • 14.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Jansson, Jan-Håkan
    Department of Public Health and Clinical Medicine, Research Unit Skellefteå, Umeå University, Umeå, Sweden.
    Söderberg, Stefan
    Department of Public Health and Clinical Medicine, Heart Centre, Umeå University, Umeå, Sweden.
    Ruge, Toralph
    Dept of Medicine Solna, Karolinska Institutet and Function of Emergency Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ärnlöv, Johan
    Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden; School of Health and Social Sciences, Dalarna University, Falun, Sweden.
    Levels of soluble tumor necrosis factor receptor 1 and 2, gender, and risk of myocardial infarction in Northern Sweden2018In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 272, p. 41-46Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS:

    Soluble receptors for tumor necrosis factor alpha (sTNFR1 and sTNFR2) have been associated with cardiovascular diseases, and some evidence points towards a difference in associated risk between men and women. We aimed to study the association between sTNFR1 and sTNFR2 and incident myocardial infarctions (MI) and to explore the influence of established cardiovascular risk factors in men and women.

    METHODS:

    We conducted a nested case control study in three large Swedish cohorts, including 533 myocardial infarction cases, and 1003 age-, sex- and cohort-matched controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated.

    RESULTS:

    An association between circulating sTNFR1 and sTNFR2 and an increased risk for MI was found when comparing cases and controls. The odds ratios were significant after adjustment for established cardiovascular risk factors and C-reactive protein in women (OR 1.44, 95% CI 1.08-1.93 for TNFR1, and 1.61, 95% CI 1.11-2.34 for TNFR2), but was abolished in men. Women with a combination of elevated CRP and values in the upper quartile of TNFR1 or TNFR2 had a 5-fold higher risk of myocardial infarction versus those with normal CRP and values in the lower three quartiles of TNFR1 or TNFR2.

    CONCLUSIONS:

    As the risk estimates for TNFR1 and TNFR2 were higher and remained significant after adjustments for established cardiovascular risk factors in women but not in men, a potential role for TNFR1 and TNFR2 in identifying women with a higher MI risk is possible. The future clinical role of TNFR1 and TNFR2 in combination with CRP to identify high risk patients for coronary heart disease has yet to be determined.

  • 15.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ruge, Toralph
    Kjøller, Erik
    Hilden, Jørgen
    Kolmos, Hans Jørn
    Sajadieh, Ahmad
    Kastrup, Jens
    Jensen, Gorm Boje
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nowak, Christoph
    Jakobsen, Janus Christian
    Winkel, Per
    Gluud, Christian
    Ärnlöv, Johan
    10-Year Associations between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients with Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy.2018In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 7, no 9, article id e008299Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)-α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease.

    METHODS AND RESULTS: CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) is a randomized clinical trial comparing clarithromycin with placebo in patients with stable coronary heart disease. The primary outcome was a composite of nonfatal acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. Patients were followed up for 10 years; discovery sample, those assigned placebo (1204 events in n=1998); and replication sample, those assigned clarithromycin (1220 events in n=1979). We used Cox regression adjusted for C-reactive protein level, established cardiovascular risk factors, kidney function, and cardiovascular drugs. After adjustments, higher serum levels of TNFR1 and TNFR2 were associated with the composite outcome in the discovery sample (hazard ratio per SD increase, 1.13; 95% confidence interval, 1.05-1.22; P=0.001 for TNFR1; hazard ratio, 1.16; 95% confidence interval, 1.08-1.24; P<0.001 for TNFR2). The associations were similar in the replication sample. The associations with the composite outcome were mainly driven by acute myocardial infarction, cardiovascular mortality, and noncardiovascular mortality. The addition of TNFR1 and TNFR2 to established cardiovascular risk factors improved prediction only modestly (<1%).

    CONCLUSIONS: Increased concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR1 and TNFR2 to improve risk prediction in these patients appears limited.

    CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00121550.

  • 16.
    Cedervall, Jessica
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Saupe, Falk
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Yanyu
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ärnlöv, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Divis Family Med, Huddinge, Sweden.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Olsson, Anna-Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.2017In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 8, article id e1320009Article in journal (Refereed)
    Abstract [en]

    Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.

  • 17. Chang, Alex R
    et al.
    Grams, Morgan E
    Ballew, Shoshana H
    Bilo, Henk
    Correa, Adolfo
    Evans, Marie
    Gutierrez, Orlando M
    Hosseinpanah, Farhad
    Iseki, Kunitoshi
    Kenealy, Timothy
    Klein, Barbara
    Kronenberg, Florian
    Lee, Brian J
    Li, Yuanying
    Miura, Katsuyuki
    Navaneethan, Sankar D
    Roderick, Paul J
    Valdivielso, Jose M
    Visseren, Frank L J
    Zhang, Luxia
    Gansevoort, Ron T
    Hallan, Stein I
    Levey, Andrew S
    Matsushita, Kunihiro
    Shalev, Varda
    Woodward, Mark
    Ärnlöv, Johan (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lannfelt, Lars (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Adiposity and risk of decline in glomerular filtration rate: meta-analysis of individual participant data in a global consortium2019In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 364, article id k5301Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the associations between adiposity measures (body mass index, waist circumference, and waist-to-height ratio) with decline in glomerular filtration rate (GFR) and with all cause mortality.

    DESIGN: Individual participant data meta-analysis.

    SETTING: Cohorts from 40 countries with data collected between 1970 and 2017.

    PARTICIPANTS: Adults in 39 general population cohorts (n=5 459 014), of which 21 (n=594 496) had data on waist circumference; six cohorts with high cardiovascular risk (n=84 417); and 18 cohorts with chronic kidney disease (n=91 607).

    MAIN OUTCOME MEASURES: GFR decline (estimated GFR decline ≥40%, initiation of kidney replacement therapy or estimated GFR <10 mL/min/1.73 m2) and all cause mortality.

    RESULTS: Over a mean follow-up of eight years, 246 607 (5.6%) individuals in the general population cohorts had GFR decline (18 118 (0.4%) end stage kidney disease events) and 782 329 (14.7%) died. Adjusting for age, sex, race, and current smoking, the hazard ratios for GFR decline comparing body mass indices 30, 35, and 40 with body mass index 25 were 1.18 (95% confidence interval 1.09 to 1.27), 1.69 (1.51 to 1.89), and 2.02 (1.80 to 2.27), respectively. Results were similar in all subgroups of estimated GFR. Associations weakened after adjustment for additional comorbidities, with respective hazard ratios of 1.03 (0.95 to 1.11), 1.28 (1.14 to 1.44), and 1.46 (1.28 to 1.67). The association between body mass index and death was J shaped, with the lowest risk at body mass index of 25. In the cohorts with high cardiovascular risk and chronic kidney disease (mean follow-up of six and four years, respectively), risk associations between higher body mass index and GFR decline were weaker than in the general population, and the association between body mass index and death was also J shaped, with the lowest risk between body mass index 25 and 30. In all cohort types, associations between higher waist circumference and higher waist-to-height ratio with GFR decline were similar to that of body mass index; however, increased risk of death was not associated with lower waist circumference or waist-to-height ratio, as was seen with body mass index.

    CONCLUSIONS: Elevated body mass index, waist circumference, and waist-to-height ratio are independent risk factors for GFR decline and death in individuals who have normal or reduced levels of estimated GFR.

  • 18.
    Christersson, Christina
    et al.
    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.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    The utility of coagulation activity for prediction of risk of mortality and cardiovascular events in guideline-treated myocardial infarction patients2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 4, p. 224-233Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite improved treatment of myocardial infarction (MI), real-world patients still suffer substantial risk for subsequent cardiovascular events. Little is known about coagulation activity shortly after MI and whether coagulation activity markers may identify patients at increased risk despite contemporary treatment.

    OBJECTIVE: To evaluate D-dimer concentration and thrombin generation potential shortly after discharge after MI and evaluate if these markers could predict the risk of future cardiovascular and bleeding events.

    METHODS: Unselected MI patients (n = 421) were included in the observational REBUS study (NCT01102933) and followed for two years. D-dimer concentrations, thrombin peak, and endogenous thrombin potential (ETP) were analyzed at inclusion (3-5 days after MI) and at early follow-up (after 2-3 weeks).

    RESULTS: Seventy-five patients (17.8%) experienced the composite endpoint (all-cause death, MI, congestive heart failure, or all-cause stroke), and 31 patients (7.4%) experienced a clinically relevant bleeding event. D-dimer concentrations at early follow-up were associated with the composite endpoint (HR [per SD increase] 1.51 [95% CI 1.22-1.87]) and with clinically relevant bleeding (HR [per SD increase] 1.80 [95% CI 1.32-2.44]). Thrombin generation potential was not significantly associated with either the composite endpoint or with clinically relevant bleeding. Higher thrombin peak and ETP at early follow-up were both inversely associated with stroke (HR [per SD increase] 0.50 [95% CI 0.30-0.81] and 0.43 [95% CI 0.22-0.83], respectively).

    CONCLUSION: In unselected MI patients treated according to contemporary guidelines, D-dimer measurements may identify patients at increased risk of new cardiovascular and bleeding events. The inverse association of thrombin generation potential and risk of stroke has to be further investigated.

  • 19.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Microparticles during long-term follow-up after acute myocardial infarction: Association to atherosclerotic burden and risk of cardiovascular events2017In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 117, no 8, p. 1571-1581Article in journal (Refereed)
    Abstract [en]

    Microparticles (MPs) are formed from platelets (PMPs), endothelial cells (EMPs) and monocytes (MMPs), and in acute myocardial infarction (MI), there is an increase of MPs in the culprit artery. In this study MPs were evaluated in whole blood in 105 patients with MI at five time-points during a two-year follow-up (FU). Patients with non-ST elevated MI had higher concentrations of CD41+MPs compared to ST elevated MI patients (p=0.024). The concentrations of PMPs in whole blood increased during the time period (p<0.001), but no significant change over time was found for EMPs and MMPs. CD62P+MP counts were higher in MI patients with diabetes (p=0.020), and patients with hypertension had increased levels of CD14+MPs (p=0.004). The amount of CD62P+TF+MPs increased significantly during FU (p<0.001). Patients with atherosclerosis in three arterial beds, i.e. coronary, carotid and peripheral arteries, had lower concentrations of CD62P+TF+MPs (p=0.035) and CD144+TF+MPs (p=0.004) compared to patients with atherosclerosis in one or two arterial beds. Higher concentrations of CD62P+MPs early after MI were associated with an increased risk of cardiovascular events during FU, hazard ratio 3.32 (95 %C11.20-9.31). Only small variations in PMP, EMP and MMP concentrations were found during long-term FU after MI and their levels seem to reflect the underlying cardiovascular disease rather than the acute MI. PMPs expressing P-selectin might be a promising biomarker for predicting future cardiovascular events, but further studies are needed to confirm these results.

  • 20.
    Cooper, Lauren B
    et al.
    Department of Medicine, Duke University School of Medicine, Durham, NC, USA..
    Savarese, Gianluigi
    Heart and Vascular Theme, Karolinska University Hospital and Department of Medicine, Unit of Cardiology, Karolinska Institutet, Stockholm, Sweden..
    Carrero, Juan-Jesus
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden..
    Szabo, Barna
    Heart-Lung Physiology Clinic, Örebro University Hospital, Örebro, Sweden..
    Jernberg, Tomas
    Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden..
    Jonsson, Åsa
    Department of Medicine, Division of Cardiology, County Hospital Ryhov, Jönköping, Sweden..
    Dahlbom, Catarina
    Strängnäs Primary Healthcare Center, Strängnäs, Sweden..
    Dahlström, Ulf
    Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lund, Lars H
    Heart and Vascular Theme, Karolinska University Hospital and Department of Medicine, Unit of Cardiology, Karolinska Institutet, Stockholm, Sweden..
    Clinical and research implications of serum versus plasma potassium measurements.2018In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844Article in journal (Refereed)
  • 21.
    Dubois, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Prostasomes as Diagnostic, Prognostic and Therapeutic Vesicles2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis explores prostasomes and their ability to be used as a new diagnostic tool for prostate cancer. Alongside diagnosis, this thesis also suggests prostasomes as a tool for prognosis and therapeutic treatment in patients with prostate cancer. By further characterizing prostasomes we can identify a biomarker and also a method of visualizing and interpreting the information provided in order to conduct a correct and fast diagnosis for prostate cancer.

    In Paper I, we show that the prostasomal bilayered membrane consists of lipid rafts, clusters that holds cholesterol, sphingolipids and gives receptors a rigid platform upon which to work. We compare the proteomic content of prostasome lipid rafts with the entire prostasome membrane in the search for a specific biomarker. 

    In Paper II, we show that purified lipid rafts from the prostasome membrane can re-vesiculate and create new bioengineered vesicles. These new vesicles can carry different agents inside them and we find that the method is also applicable to blood cells. This suggests a new method for cell-specific delivery of drugs and cancer therapy. 

    In Paper III, we further characterize the prostasome membrane, this time mapping purinergic receptors. This could be used in the development of prostate cancer treatment and to gain better understanding of how prostasomes interact with surrounding cells in their ambient environment.

    In Paper IV, we investigate the difference in thymidine kinase 1 (TK1) enzyme activity between prostasomes and malignant exosomes. TK1 is considered to be a biomarker of cell proliferation and could therefore be used as a biomarker for prostate cancer diagnosis and progression.

    In summary, this thesis contributes to the puzzle of how to better diagnose, prognose and treat prostate cancer. Although it is mainly pre-clinical research it opens up new possibilities for the diagnosis and treatment of prostate cancer.

  • 22.
    Dubois, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Occurrence of purinergic receptors in human prostasomes (prostate epithelial cell derived exosomes)Manuscript (preprint) (Other academic)
  • 23.
    Dubois, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Occurrence of purinergic receptors in human prostasomes (prostate epithelial cell-derived exosomes)2018In: Article in journal (Refereed)
  • 24.
    Dubois, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hultenby, Kjell
    Department of Laboratory Medicine, Karolinska Institutet, SE-141 86 Huddinge, Sweden.
    Waldenström, Anders
    Department of Public Health and Clinical Medicine, Umeå University, SE-901 85 Umeå, Sweden.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, K. Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Human erythrocyte-derived nanovesicles can readily be loaded with doxorubicin and act as anticancer agents2018In: Cancer Research Frontiers, ISSN 2328-5249, Vol. 4, no 1, p. 13-26Article in journal (Refereed)
    Abstract [en]

    Purpose: In future therapeutics new formulas are needed that assure lower doses, fewer side effects, targeted administration and protection of the drug from degradation. In a first step to fulfil the requirements defined above, we carried out an in vitro study by developing a new procedure to encapsulate drugs using native vesicles first from prostasomes and then from erythrocyte membranes known to be well tolerated. The new method for production of drug delivery vesicles utilized osmotic loading of detergent resistant membranes (DRMs).

    Materials and methods: DRMs of prostasomes and prepared human erythrocyte membranes were extracted and separated in a sucrose gradient at a density of 1.10 g/mL containing 1% Triton X-100. These DRMs were characterized by electron microscopy (transmission and scanning EM) and loaded with low and high molecular compounds. PC3 prostate cancer cells were treated with doxorubicin loaded DRMs in triplicate. DAPI (nuclear fluorescent stain) was included and fluorescence microscopic pictures were taken before the cells were trypsinized and counted after 48h.

    Results: The content of the well separated band was observed ultrastructurally as small spherical, double layered membrane vesicles, (DRM vesicles) which harbored hyperosmolar sucrose of the gradient. Encapsulated hyperosmolar sucrose induced a transient osmotic lysis of the DRM vesicles when suspended in isotonic buffer containing loading molecules allowing vesicular inclusion. After this proof of concept, the method was finally employed for doxorubicin loading of DRM vesicles from human erythrocytes. When incubating such vesicles with PC3 cells a complete arrest of growth was observed in sharp contrast to PC3 cells incubated with plain doxorubicin in similar conditions.

    Conclusion: The present results open up new possibilities for using DRM vesicles as drug delivery vesicles.

  • 25.
    Dubois, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Manouchehri Doulabi, Ehsan
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Löf, Liza
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kamali-Moghaddam, Masood
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Stålhandske, Per
    Biovica International AB.
    Increased Levels of Thymidine Kinase 1 in Malignant Cell-derived ExosomesManuscript (preprint) (Other academic)
  • 26.
    Dubois, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Manouchehri Doulabi, Ehsan
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Löf, Liza
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kamali-Moghaddam, Masood
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Stålhandske, Per
    Biovica International AB.
    Increased levels of thymidine kinase 1 in malignant cell-derived exosomesManuscript (preprint) (Other academic)
  • 27.
    Eggers, Kai M.
    et al.
    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.
    Lindahl, Bertil
    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.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Predictors of 10-year changes in levels of N-terminal pro B-type natriuretic peptide and cardiac troponin I in the elderly2018In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 257, p. 300-305Article in journal (Refereed)
    Abstract [en]

    Background: Measurement of N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) might be useful for monitoring of cardiovascular disease in the elderly. However, it is not clear whether changes in these biomarkers are associated with changes in the cardiovascular risk profile and if this pattern could be modified by changes in lifestyle habits or medications.

    Methods: We measured levels of NT-proBNP and cTnI in community-dwelling subjects (PIVUS study) upon visits scheduled at age 70 (n = 1007), 75 (n = 825) and 80 (n = 602). The associations of these biomarkers with repeated measurements of clinical variables (risk factors, lifestyle habits, echocardiographic data and medications) were investigated using sex-adjusted linear mixed random effect models.

    Results: NT-proBNP and cTnI were positively associated with increasing age. NT-proBNP, but not cTnI, was affected by changes of renal function and the degree of obesity. NT-proBNP was more closely related than cTnI to changes in echocardiographic estimates of cardiac geometry and function. Biomarker levels and/or their changes were inversely associated with a physically more active lifestyle (both NT-proBNP and cTnI) and statin treatment at age 70 (only cTnI). Changes in smoking status or antihypertensive treatment had no effect on biomarker levels.

    Conclusions: Changes in NT-proBNP and cTnI levels are associated with different patterns of cardiovascular disease burden when using a longitudinal approach. However, levels of both biomarkers and their changes also reflect changes in the cardiovascular risk profile that might be modifiable. This is an important aspect for the use of any cardiovascular biomarker in an elderly population.

  • 28.
    Emami Khoonsari, Payam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Proteomics Studies of Subjects with Alzheimer’s Disease and Chronic Pain2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alzheimer’s disease (AD) is a neurodegenerative disease and the major cause of dementia, affecting more than 50 million people worldwide. Chronic pain is long-lasting, persistent pain that affects more than 1.5 billion of the world population. Overlapping and heterogenous symptoms of AD and chronic pain conditions complicate their diagnosis, emphasizing the need for more specific biomarkers to improve the diagnosis and understand the disease mechanisms.

    To characterize disease pathology of AD, we measured the protein changes in the temporal neocortex region of the brain of AD subjects using mass spectrometry (MS). We found proteins involved in exo-endocytic and extracellular vesicle functions displaying altered levels in the AD brain, potentially resulting in neuronal dysfunction and cell death in AD.

    To detect novel biomarkers for AD, we used MS to analyze cerebrospinal fluid (CSF) of AD patients and found decreased levels of eight proteins compared to controls, potentially indicating abnormal activity of complement system in AD.

    By integrating new proteomics markers with absolute levels of Aβ42, total tau (t-tau) and p-tau in CSF, we improved the prediction accuracy from 83% to 92% of early diagnosis of AD. We found increased levels of chitinase-3-like protein 1 (CH3L1) and decreased levels of neurosecretory protein VGF (VGF) in AD compared to controls.

    By exploring the CSF proteome of neuropathic pain patients before and after successful spinal cord stimulation (SCS) treatment, we found altered levels of twelve proteins, involved in neuroprotection, synaptic plasticity, nociceptive signaling and immune regulation.

    To detect biomarkers for diagnosing a chronic pain state known as fibromyalgia (FM), we analyzed the CSF of FM patients using MS. We found altered levels of four proteins, representing novel biomarkers for diagnosing FM. These proteins are involved in inflammatory mechanisms, energy metabolism and neuropeptide signaling.

    Finally, to facilitate fast and robust large-scale omics data handling, we developed an e-infrastructure. We demonstrated that the e-infrastructure provides high scalability, flexibility and it can be applied in virtually any fields including proteomics. This thesis demonstrates that proteomics is a promising approach for gaining deeper insight into mechanisms of nervous system disorders and find biomarkers for diagnosis of such diseases.

  • 29.
    Emami Khoonsari, Payam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Musunri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Herman, Stephanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Svensson, Camilla I
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden..
    Tanum, Lars
    Department of R&D in Mental Health, Akershus University Hospital, Lørenskog, Norway..
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Systematic Analysis of the Cerebrospinal Fluid Proteome of Fibromyalgia patients2019In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, p. 35-43Article in journal (Refereed)
    Abstract [en]

    Fibromyalgia (FM) is a syndrome characterized by widespread muscular pain, fatigue and functional symptoms, which is known to be difficult to diagnose as the various symptoms overlap with many other conditions. Currently, there are no biomarkers for FM, and the diagnosis is made subjectively by the clinicians. We have performed shotgun proteomics on cerebrospinal fluid (CSF) from FM patients and non-pain controls to find potential biomarker candidates for this syndrome. Based on our multivariate and univariate analyses, we found that the relative differences in the CSF proteome between FM patients and controls were moderate. Four proteins, important to discriminate FM patients from non-pain controls, were found: Apolipoprotein C-III, Galectin-3-binding protein, Malate dehydrogenase cytoplasmic and the neuropeptide precursor protein ProSAAS. These proteins are involved in lipoprotein lipase (LPL) activity, inflammatory signaling, energy metabolism and neuropeptide signaling.

  • 30.
    Emami Khoonsari, Payam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Ossipova, Elena
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Clin, Unit Rheumatol,Dept Med, Stockholm, Sweden.
    Lengqvist, Johan
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Clin, Unit Rheumatol,Dept Med, Stockholm, Sweden.
    Svensson, Camilla, I
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Kosek, Eva
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Kadetoff, Diana
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Jakobsson, Per-Johan
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Clin, Unit Rheumatol,Dept Med, Stockholm, Sweden.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lampa, Jon
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Clin, Unit Rheumatol,Dept Med, Stockholm, Sweden.
    The human CSF pain proteome2019In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 190, p. 67-76Article in journal (Refereed)
    Abstract [en]

    Chronic pain represents one of the major medical challenges in the 21st century, affecting > 1.5 billion of the world population. Overlapping and heterogenous symptoms of various chronic pain conditions complicate their diagnosis, emphasizing the need for more specific biomarkers to improve the diagnosis and understand the disease mechanisms. We have here investigated proteins found in human CSF with respect to known "pain" genes and in a cohort of patients with dysfunctional pain (fibromyalgia, FM), inflammatory pain (rheumatoid arthritis patients, RA) and non-pain controls utilized semi-quantitative proteomics using mass spectrometry (MS) to explore quantitative differences between these cohorts of patients. We found that "pain proteins" detected in CSF using MS are typically related to synaptic transmission, inflammatory responses, neuropeptide signaling- and hormonal activity. In addition, we found ten proteins potentially associated with chronic pain in FM and RA: neural cell adhesion molecule L1, complement C4-A, lysozyme C, receptor-type tyrosine-protein phosphatase zeta, apolipoprotein D, alpha-1-antichymotrypsin, granulins, calcium/calmodulin-dependent protein kinase type II subunit alpha, mast/stem cell growth factor receptor Kit, prolow-density lipoprotein receptor-related protein 1. These proteins might be of importance for understanding the mechanisms of dysfunctional/inflammatory chronic pain and also for use as potential biomarkers. Significance: Chronic pain is a common disease and it poses a large burden on worldwide health. Fibromyalgia (FM) is a heterogeneous disease of unknown etiology characterized by chronic widespread pain (CWP). The diagnosis and treatment of FM is based on the analysis of clinical assessments and no measurable biomarkers are available. Cerebrospinal fluid (CSF) has been historically considered as a rich source of biomarkers for diseases of nervous system including chronic pain. Here, we explore CSF proteome of FM patients utilizing mass spectrometry based quantitative proteomics method combined with multivariate data analysis in order to monitor the dynamics of the CSF proteome. Our findings in this exploratory study support notable presence of pain related proteins in CSF yet with specific domains including inflammatory responses, neuropeptide signaling- and hormonal activity. We have investigated molecular functions of significantly altered proteins and demonstrate presence of 176 known pain related proteins in CSF. In addition, we found ten proteins potentially associated with pain in FM and RA: neural cell adhesion molecule L1, complement C4-A, lysozyme C, receptor-type tyrosine-protein phosphatase zeta, apolipoprotein D, alpha-1-antichymotrypsin, granulins, calcium/calmodulindependent protein kinase type II subunit alpha, mast/stem cell growth factor receptor Kit, prolow-density lipoprotein receptor-related protein 1. These proteins are novel in the context of FM but are known to be involved in pain mechanisms including inflammatory response and signal transduction. These results should be of clear significance and interest for researchers and clinicians working in the field of pain utilizing human CSF and MS based proteomics.

  • 31.
    Emami Khoonsari, Payam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Herman, Stephanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Remnestal, Julia
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, SciLifeLab, Stockholm, Sweden.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Brundin, RoseMarie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Degerman Gunnarsson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Zetterberge, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Mölndal, Sweden; Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden; UK Dementia Res Inst UCL, London, England; UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England.
    Nilsson, Peter
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, SciLifeLab, Stockholm, Sweden.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers2019In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 67, no 2, p. 639-651Article in journal (Refereed)
    Abstract [en]

    Background: Alzheimer’s disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD.

    Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects.

    Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4–9 years and 21 of these converted to AD, whereas 53 remained stable.

    Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively.

    Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

  • 32.
    Eriksson, Mats B
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Strandberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    The effect of hemorrhagic shock and intraosseous adrenaline injection on the delivery of a subsequently administered drug - an experimental study2019In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 27, article id 29Article in journal (Refereed)
    Abstract [en]

    Background: Intraosseous (IO) access is a recommended method when venous access cannot be rapidly established in an emergency. Experimental data suggest that major hemorrhage and catecholamine administration both reduce bone marrow blood flow. We studied the uptake of gentamicin as a tracer substance administered IO following adrenaline administration in hemorrhagic shock and in cardiac arrest.

    Methods: Twenty anesthetized pigs underwent hemorrhage corresponding to 50% of the blood volume. They then received injections of either; adrenaline IO (n=5), saline IO n=5), adrenaline IO during cardiac arrest and cardiopulmonary resuscitation (CPR, n=5), or intravenous adrenaline. The injections were followed by an injection of gentamicin by the same route. Doses and volumes were equivalent among the groups. In all animals, mixed venous antibiotic concentrations were analyzed at 5, 15 and 30min after administration.

    Results: Mean (SD) plasma gentamicin concentrations (mg x L-1) at 5min were 26.4 (2.3) in the group with previous IO adrenaline administration, 26.6 (4.5) in the IO saline group, 31. 2 (12) in the IO adrenaline + CPR group and 23 (4.5) in the IV group. Concentrations in the CPR group were significantly higher than the others.

    Conclusions: No impairment of drug uptake with IO administration after recent IO adrenaline exposure was demonstrable in this shock model.

  • 33.
    Fall, Tove
    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.
    Hedman, Anna
    Karolinska Institutet.
    Pershagen, Göran
    Karolinska Institutet.
    Andolf, Ellika
    Karolinska Institutet.
    Almqvist, Catarina
    Karolinska Institutet.
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Reference Intervals for Fecal Calprotectin in Pregnant Women Using a Particle Enhanced Turbidimetric Assay2019In: Clinical Laboratory, ISSN 1433-6510, Vol. 65, no 7, p. 1293-1297Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fecal calprotectin is widely used as a marker for inflammatory bowel diseases (IBD). IBD often affects women during their reproductive years, but there are no established reference intervals during pregnancy. The aim of the present study was to define reference values during pregnancy and in the postpartum period to allow comparisons between patient results and reference values.

    METHODS: Fecal samples were collected from 84 healthy females during pregnancy week 26 to 28 and a second sample was collected six months after delivery. The samples were weighed, extracted, and centrifugated to remove debris. The extracted samples were then analyzed on a chemistry analyzer using a particle enhanced turbidimetric immunoassay reagent.

    RESULTS: The calculated reference interval during pregnancy was < 127 μg/g (90% confidence interval, 90 - 164 μg/g) and the corresponding reference interval during the postpartum period was < 143 μg/g (60 - 226 μg/g). There were no significant statistical differences between F-calprotectin values analyzed at the two sampling times.

    CONCLUSIONS: The reference values are slightly higher than the cutoff values of 50 - 100 μg/g often used as General cutoff for fecal calprotectin.

  • 34. Feigin, VL
    et al.
    Abate, KH
    Abd-Allah, F
    Abdulle, AM
    Abera, SF
    Abyu, GY
    Ahmed, MB
    Aichour, AN
    Aichour, I
    Aichour, MTE
    Akinyemi, RO
    Alabed, S
    Al-Raddadi, R
    Alvis-Guzman, N
    Amare, AT
    Ärnlöv, Johan
    Karolinska institute; Dalarna university.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Yimam, HH, ,
    Yonemoto, N,
    Yu, C,
    Zaidi, Z
    El Sayed Zaki, M
    Zunt, JR
    Murray, CJL
    Vos, T
    Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.2017In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 16, no 11, p. 877-897Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level.

    METHODS: We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development.

    FINDINGS: Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs.

    INTERPRETATION: Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services.

    FUNDING: Bill & Melinda Gates Foundation.

  • 35.
    Feresiadou, Amalia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Press, Rayomand
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..
    Kmezic, Ivan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..
    Nygren, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Svenningsson, Anders
    Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden..
    Niemelä, Valter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease2019In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 332, p. 31-36Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases.

    METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease.

    RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL.

    CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.

  • 36.
    Frithiof, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Bandert, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Smekal, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Central Venous Line and Dialysis Catheter Position Affects Drug Clearance during Continuous Renal Replacement Therapy in an Animal Model.2019In: ASAIO journal (1992), ISSN 1058-2916, E-ISSN 1538-943X, Vol. 65, no 4, p. 408-413Article in journal (Refereed)
    Abstract [en]

    In intensive care, drugs are commonly administered through central venous catheters (CVC). These catheters and central venous dialysis catheters (CVDC) are often placed in the same vessel for practical reasons. The aim of this experimental study was to investigate if the position of CVC and CVDC influences the elimination of infused drugs, during continuous renal replacement therapy (CRRT). In a randomized, cross-over model, anesthetized piglets received both a CVC and a CVDC in a jugular vein. Another CVDC was placed in a femoral vein for comparison. After baseline measurements, CRRT was performed in either of the CVDC, each CRRT-period separated by another baseline period. Hypotension was induced by peripherally given sodium nitroprusside. In the CVC, both gentamicin and noradrenaline were administered. Noradrenaline was titrated to reach a target blood pressure. When CRRT was performed using the CVDC in the same vessel as the drugs were infused, the plasma concentration of gentamicin was reduced compared with when the infusion and CVDC were in different vessels (5.66 [standard deviation (SD) ± 1.23] vs. 7.76 [SD ± 2.30] mg/L [p = 0.02]). The noradrenaline infusion rate needed to reach the target blood pressure was more than doubled (0.32 [SD ± 0.16] vs. 0.15 [SD ± 0.08] µg/kg/min [p = 0.006]). This experimental study indicates that the removal of drugs is increased if infusion is in close vicinity of the CVDC, during CRRT.

  • 37. Fullman, N
    et al.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Murray, Christopher J L
    Measuring progress and projecting attainment on the basis of past trends of the health-related Sustainable Development Goals in 188 countries: an analysis from the Global Burden of Disease Study 2016.2017In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 390, no 10100, p. 1423-1459Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The UN's Sustainable Development Goals (SDGs) are grounded in the global ambition of "leaving no one behind". Understanding today's gains and gaps for the health-related SDGs is essential for decision makers as they aim to improve the health of populations. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016), we measured 37 of the 50 health-related SDG indicators over the period 1990-2016 for 188 countries, and then on the basis of these past trends, we projected indicators to 2030.

    METHODS: We used standardised GBD 2016 methods to measure 37 health-related indicators from 1990 to 2016, an increase of four indicators since GBD 2015. We substantially revised the universal health coverage (UHC) measure, which focuses on coverage of essential health services, to also represent personal health-care access and quality for several non-communicable diseases. We transformed each indicator on a scale of 0-100, with 0 as the 2·5th percentile estimated between 1990 and 2030, and 100 as the 97·5th percentile during that time. An index representing all 37 health-related SDG indicators was constructed by taking the geometric mean of scaled indicators by target. On the basis of past trends, we produced projections of indicator values, using a weighted average of the indicator and country-specific annualised rates of change from 1990 to 2016 with weights for each annual rate of change based on out-of-sample validity. 24 of the currently measured health-related SDG indicators have defined SDG targets, against which we assessed attainment.

    FINDINGS: Globally, the median health-related SDG index was 56·7 (IQR 31·9-66·8) in 2016 and country-level performance markedly varied, with Singapore (86·8, 95% uncertainty interval 84·6-88·9), Iceland (86·0, 84·1-87·6), and Sweden (85·6, 81·8-87·8) having the highest levels in 2016 and Afghanistan (10·9, 9·6-11·9), the Central African Republic (11·0, 8·8-13·8), and Somalia (11·3, 9·5-13·1) recording the lowest. Between 2000 and 2016, notable improvements in the UHC index were achieved by several countries, including Cambodia, Rwanda, Equatorial Guinea, Laos, Turkey, and China; however, a number of countries, such as Lesotho and the Central African Republic, but also high-income countries, such as the USA, showed minimal gains. Based on projections of past trends, the median number of SDG targets attained in 2030 was five (IQR 2-8) of the 24 defined targets currently measured. Globally, projected target attainment considerably varied by SDG indicator, ranging from more than 60% of countries projected to reach targets for under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria, to less than 5% of countries projected to achieve targets linked to 11 indicator targets, including those for childhood overweight, tuberculosis, and road injury mortality. For several of the health-related SDGs, meeting defined targets hinges upon substantially faster progress than what most countries have achieved in the past.

    INTERPRETATION: GBD 2016 provides an updated and expanded evidence base on where the world currently stands in terms of the health-related SDGs. Our improved measure of UHC offers a basis to monitor the expansion of health services necessary to meet the SDGs. Based on past rates of progress, many places are facing challenges in meeting defined health-related SDG targets, particularly among countries that are the worst off. In view of the early stages of SDG implementation, however, opportunity remains to take actions to accelerate progress, as shown by the catalytic effects of adopting the Millennium Development Goals after 2000. With the SDGs' broader, bolder development agenda, multisectoral commitments and investments are vital to make the health-related SDGs within reach of all populations.

  • 38.
    Fullman, Nancy
    et al.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Yearwood, Jamal
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Abay, Solomon M.
    Addis Ababa Univ, Addis Ababa, Ethiopia.
    Abbafati, Cristiana
    Univ Roma La Sapienza, Rome, Italy.
    Abd-Allah, Foad
    Cairo Univ, Dept Neurol, Cairo, Egypt.
    Abdela, Jemal
    Haramaya Univ, Coll Hlth & Med Sci, Harar, Ethiopia.
    Abdelalim, Ahmed
    Cairo Univ, Dept Neurol, Cairo, Egypt.
    Abebe, Zegeye
    Univ Gondar, Gondar, Ethiopia.
    Abebo, Teshome Abuka
    Hawassa Univ, Coll Med & Hlth Sci, Hawassa, Ethiopia.
    Aboyans, Victor
    Dupuytren Univ Hosp, Limoges, France.
    Abraha, Haftom Niguse
    Mekelle Univ, Mekelle, Ethiopia.
    Abreu, Daisy M. X.
    Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil.
    Abu-Raddad, Laith J.
    Weill Cornell Med Coll Qatar, Infect Dis Epidemiol Grp, Doha, Qatar.
    Adane, Akilew Awoke
    Univ Gondar, Gondar, Ethiopia;Univ Queensland, Brisbane, Qld, Australia.
    Adedoyin, Rufus Adesoji
    Obafemi Awolowo Univ, Dept Med Rehabil, Ife, Nigeria.
    Adetokunboh, Olatunji
    Stellenbosch Univ, Cape Town, South Africa.
    Adhikari, Tara Ballav
    Univ Southern Denmark, Fac Hlth Sci, Unit Hlth Promot Res, Esbjerg, Denmark.
    Afarideh, Mohsen
    Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Tehran, Iran.
    Afshin, Ashkan
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Agarwal, Gina
    McMaster Univ, Hamilton, ON, Canada;CSIR, Inst Genom & Integrat Biol, Delhi, India;Baylor Coll Med, Dept Internal Med, Houston, TX 77030 USA;Indian Inst Publ Hlth, Gurugram, India;Publ Hlth Fdn India, Gurugram, India.
    Agius, Dominic
    Directorate Hlth Informat & Res, Pieta, Malta;Malta Coll Family Doctors, Gzira, Malta.
    Agrawal, Anurag
    Agrawal, Sutapa
    Kiadaliri, Aliasghar Ahmad
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Dept Clin Sci Lund,Orthoped,Clin Epidemiol Unit,N, Lund, Sweden.
    Aichour, Miloud Taki Eddine
    High Natl Sch Vet Med, Algiers, Algeria.
    Akibu, Mohammed
    Debere Berhan Univ, Debre Berhan, Ethiopia.
    Akinyemi, Rufus Olusola
    Univ Ibadan, Ibadan, Nigeria;Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England.
    Akinyemiju, Tomi F.
    Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA.
    Akseer, Nadia
    Hosp Sick Children, Ctr Global Child Hlth, Toronto, ON, Canada;Univ Toronto, Fac Med, Dalla Lana Sch Publ Hlth, Dept Nutr Sci, Toronto, ON, Canada.
    Al Lami, Faris Hasan
    Baghdad Coll Med, Baghdad, Iraq.
    Alahdab, Fares
    Mayo Clin, Fdn Med Educ & Res, Rochester, MN USA;Syrian Amer Med Soc, Washington, DC USA.
    Al-Aly, Ziyad
    Washington Univ St Louis, St Louis, MO USA.
    Alam, Khurshid
    Univ Western Australia, Sch Populat & Global Hlth, Perth, WA, Australia.
    Alam, Tahiya
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Alasfoor, Deena
    Minist Hlth, Int Relat Div, Al Khuwair, Oman.
    Albittar, Mohammed I.
    Alene, Kefyalew Addis
    Univ Gondar, Inst Publ Hlth, Dept Epidemiol & Biostat, Gondar, Ethiopia;Australian Natl Univ, Res Sch Populat Hlth, Dept Global Hlth, Canberra, ACT, Australia.
    Al-Eyadhy, Ayman
    King Saud Univ, Riyadh, Saudi Arabia;King Faisal Specialist Hosp & Res Ctr, Riyadh, Saudi Arabia.
    Ali, Syed Danish
    Univ London, London, England;SIR Management Consultants, Oxford, England;Inst & Fac Actuaries, Oxford, England.
    Alijanzadeh, Mehran
    Qazvin Univ Med Sci, Qavin, Iran.
    Aljunid, Syed M.
    Kuwait Univ, Fac Publ Hlth, Kuwait, Kuwait;Natl Univ Malaysia, Int Ctr Casemix & Clin Coding, Kuala Lumpur, Malaysia.
    Alkerwi, Ala'a
    Luxembourg Inst Hlth, Strassen, Luxembourg.
    Alla, Francois
    Univ Lorraine, Sch Publ Hlth, Nancy, France.
    Allebeck, Peter
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden.
    Allen, Christine
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Alomari, Mahmoud A.
    Jordan Univ Sci & Technol, Fac Appl Med Sci, Dept Rehabil Sci, Div Phys Therapy, Irbid, Jordan.
    Al-Raddadi, Rajaa
    King Abdulaziz Univ, Dept Family & Community Med, Coll Med, Jeddah, Saudi Arabia.
    Alsharif, Ubai
    Charite Univ Med Berlin, Berlin, Germany.
    Altirkawi, Khalid A.
    King Saud Univ, Riyadh, Saudi Arabia.
    Alvis-Guzman, Nelson
    Univ Cartagena, Cartagena De Indias, Colombia.
    Amare, Azmeraw T.
    Bahir Dar Univ, Coll Med & Hlth Sci, Bahir Dar, Ethiopia.
    Amenu, Kebede
    Ammar, Walid
    Minist Publ Hlth, Beirut, Lebanon.
    Amoako, Yaw Ampem
    Komfo Anokye Teaching Hosp, Dept Med, Kumasi, Ghana.
    Anber, Nahla
    Andrei, Catalina Liliana
    Carol Davila Univ Med & Pharm, Bucharest, Romania.
    Androudi, Sofia
    Univ Thessaly, Larisa, Greece.
    Antonio, Carl Abelardo T.
    Univ Philippines Manila, Coll Publ Hlth, Manila, Philippines;Univ Philippines Manila, Coll Publ Hlth, Dept Hlth Policy & Adm, Manila, Philippines.
    Araujo, Valdelaine E. M.
    Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil;Minist Hlth Brazil, Brasilia, DF, Brazil.
    Aremu, Olatunde
    Birmingham City Univ Dept Publ Hlth & Therapies, Birmingham, W Midlands, England.
    Arnlov, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Stockholm, Sweden;Dalama Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Artaman, Al
    Univ Manitoba, Winnipeg, MB, Canada.
    Aryal, Krishna Kumar
    Nepal Hlth Res Council, Kathmandu, Nepal;Univ Oslo, Oslo, Norway.
    Asayesh, Hamid
    Qom Univ Med Sci, Sch Paramed, Dept Emergency Med, Qom, Iran.
    Asfaw, Ephrem Tsegay
    Mekelle Univ, Coll Hlth Sci, Mekelle, Ethiopia;Mekelle Univ, Inst Biomed Sci, Mekelle, Ethiopia.
    Asgedom, Solomon Weldegebreal
    Mekelle Univ, Mekelle, Ethiopia.
    Asghar, Rana Jawad
    South Asian Publ Hlth Forum, Islamabad, Pakistan.
    Ashebir, Mengistu Mitiku
    Mekelle Univ, Sch Publ Hlth, Mekelle, Ethiopia.
    Asseffa, Netsanet Abera
    Atey, Tesfay Mehari
    Atre, Sachin R.
    Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Clin Global Hlth Educ, Baltimore, MD USA;Dr D Y Patil Vidyapeeth Pune, Pune, Maharashtra, India.
    Atteraya, Madhu S.
    Keimyung Univ, Daegu, South Korea.
    Avila-Burgos, Leticia
    Natl Inst Publ Hlth, Cuemavaca, Mexico.
    Avokpaho, Euripide Frinel G. Arthur
    Inst Rech Clin Benin, Cotonou, Benin;Lab Etudes & Rech Act St LERAS Afrique, Parakou, Benin.
    Awasthi, Ashish
    Indian Inst Publ Hlth, Gandhinagar, India.
    Quintanilla, Beatriz Paulina Ayala
    La Trobe Univ, Judith Lumley Ctr Mother Infant & Family Hlth Res, Melbourne, Vic, Australia;Peruvian Natl Inst Hlth, Lima, Peru.
    Ayalew, Animut Alebel
    Debre Markos Univ, Debre Markos, Ethiopia.
    Ayele, Henok Tadesse
    McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada;Dilla Univ, Dilla, Ethiopia.
    Ayer, Rakesh
    Univ Tokyo, Tokyo, Japan.
    Ayuk, Tambe Betrand
    Inst Med Res & Plant Med Studies Cameroon, Yaounde, Cameroon;Univ South Africa, Pretoria, South Africa.
    Azzopardi, Peter
    Burnet Inst, Melbourne, Vic, Australia;Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia;Univ Melbourne, Murdoch Childrens Res Inst, Melbourne, Vic, Australia;South Australian Hlth & Med Res Inst, Wardliparingga Aboriginal Res Unit, Adelaide, SA, Australia.
    Azzopardi-Muscat, Natasha
    Directorate Hlth Informat & Res, Pieta, Malta;Univ Malta, Isl & Small States Inst, Dept Hlth Serv Management, Msida, Malta.
    Babalola, Tesleem Kayode
    Univ Lagos, Dept Community Hlth & Primary Care, Lagos, Nigeria.
    Badali, Hamid
    Invas Fungi Res Ctr, Sari, Iran;Ctr Expertise Mycol Radboudumc CWZ, Nijmegen, Netherlands.
    Badawi, Alaa
    Univ Toronto, Fac Med, Dalla Lana Sch Publ Hlth, Dept Nutr Sci, Toronto, ON, Canada;Publ Hlth Agcy Canada, Toronto, ON, Canada.
    Banach, Maciej
    Med Univ Lodz, Dept Hypertens, Lodz, Poland.
    Banerjee, Amitava
    UCL, Inst Hlth Informat, Farr Inst Hlth Informat Res, London, England.
    Banstola, Amrit
    Publ Hlth Perspect Nepal, Pokhara, Nepal.
    Barber, Ryan M.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Barboza, Miguel A.
    Hosp Dr Rafael A Calderon Guardia, CCSS, San Jose, Costa Rica;Univ Costa Rica, San Pedro, Costa Rica.
    Barker-Collo, Suzanne L.
    Univ Auckland, Sch Psychol, Auckland, New Zealand.
    Baernighausen, Till
    Barquera, Simon
    Natl Inst Publ Hlth, Cuemavaca, Mexico.
    Barrero, Lope H.
    Pontificia Univ Javeriana, Sch Engn, Dept Ind Engn, Bogota, Colombia.
    Bassat, Quique
    Univ Barcelona, Barcelona Inst Global Hlth, Barcelona, Spain;ICREA, Barcelona, Spain.
    Basu, Sanjay
    Stanford Univ, Stanford, CA USA.
    Baune, Bernhard T.
    Univ Adelaide, Sch Med, Discipline Psychiat, Adelaide, SA, Australia.
    Bazargan-Hejazi, Shahrzad
    Charles R Drew Univ Med & Sci, Coll Med, Los Angeles, CA USA;Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA.
    Bedi, Neeraj
    Jazan Univ, Coll Publ Hlth & Trop Med, Jazan, Saudi Arabia.
    Beghi, Ettore
    IRCCS, Ist Ric Farmacol Mario Negri, Milan, Italy.
    Behzadifar, Masoud
    Lorestan Univ Med Sci, Social Determinants Hlth Res Ctr, Khorramabad, Iran;Lorestan Univ Med Sci, Khorramabad, Iran;Iran Univ Med Sci, Hlth Management & Econ Res Ctr, Tehran, Iran.
    Behzadifar, Meysam
    Bekele, Bayu Begashaw
    Univ Gondar, Coll Med & Hlth Sci, Gondar, Ethiopia;Mizan Tepi Univ, Mizan Aman, Ethiopia.
    Belachew, Abate Bekele
    Mekelle Univ, Sch Publ Hlth, Mekelle, Ethiopia.
    Belay, Saba Abraham
    Dr Tewelde Legesse Hlth Sci Coll, Mekelle, Ethiopia.
    Belay, Yihalem Abebe
    Debre Markos Univ, Debre Markos, Ethiopia.
    Bell, Michelle L.
    Yale Univ, New Haven, CT USA.
    Bello, Aminu K.
    Univ Alberta, Edmonton, AB, Canada.
    Bennett, Derrick A.
    Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England.
    Bennett, James R.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Bensenor, Isabela M.
    Univ Sao Paulo, Sao Paulo, Brazil.
    Berhe, Derbew Fikadu
    Mekelle Univ, Sch Pharm, Mekelle, Ethiopia;Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands.
    Bernabe, Eduardo
    Kings Coll London, London, England.
    Bernstein, Robert Steven
    Emory Univ, Rollins Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA;Univ South Honda, Coll Publ Hlth, Dept Global Hlth, Tampa, FL USA.
    Beuran, Mircea
    Carol Davila Univ Med & Pharm, Bucharest, Romania;Emergency Hosp Bucharest, Bucharest, Romania.
    Bhalla, Ashish
    Postgrad Inst Med Educ & Res, Chandigarh, India.
    Bhatt, Paurvi
    Medtron Philanthropy, Minneapolis, MN USA.
    Bhaumik, Soumyadeep
    Publ Hlth Fdn India, Gurugram, India.
    Bhutta, Zulfiqar A.
    Hosp Sick Children, Ctr Global Child Hlth, Toronto, ON, Canada;Aga Khan Univ, Ctr Excellence Women & Child Hlth, Karachi, Pakistan.
    Biadgo, Belete
    Univ Gondar, Gondar, Ethiopia.
    Bijani, Ali
    Babol Univ Med Sci, Social Determinants Hlth Res Ctr, Hlth Res Inst, Babol Sar, Iran.
    Bikbov, Boris
    IRCCS, Ist Ric Farmacol Mario Negri, Milan, Italy.
    Birungi, Charles
    UCL, London, England.
    Biryukov, Stan
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Bizuneh, Hailemichael
    St Pauls Hosp, Millennium Med Coll, Addis Ababa, Ethiopia;Jigjiga Univ, Jigjiga, Ethiopia.
    Bolliger, Ian W.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Bolt, Kaylin
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Bou-Orm, Ibrahim R.
    Minist Publ Hlth, Beirut, Lebanon.
    Bozorgmehr, Kayvan
    Univ Heidelberg Hosp, Dept Gen Practice & Hlth Serv Res, Heidelberg, Germany.
    Brady, Oliver Jerome
    London Sch Hyg & Trop Med, London, England.
    Brazinova, Alexandra
    Comenius Univ, Inst Epidemiol, Fac Med, Bratislava, Slovakia.
    Breitborde, Nicholas J. K.
    Ohio State Univ, Columbus, OH 43210 USA.
    Brenner, Hermann
    German Canc Res Ctr, Heidelberg, Germany.
    Britton, Gabrielle
    INDICASAT AIP, Panama City, Panama.
    Brugha, Traolach S.
    Univ Leicester, Leicester, Leics, England.
    Butt, Zahid A.
    Al Shifa Trust Eye Hosp, Rawalpindi, Pakistan.
    Cahuana-Hurtado, Lucero
    Natl Inst Publ Hlth, Cuemavaca, Mexico.
    Campos-Nonato, Ismael Ricardo
    Natl Inst Publ Hlth, Cuemavaca, Mexico;Harvard Univ, Harvard T H Chan Sch Publ Hlth, Boston, MA 02115 USA. Africa Hlth Res Inst, Mtubatuba, South Africa.
    Campuzano, Julio Cesar
    Natl Inst Publ Hlth, Cuemavaca, Mexico.
    Car, Josip
    Nanyang Technol Univ, LKCMed, Singapore, Singapore;Imperial Coll London, London, England.
    Car, Mate
    Imperial Coll London, London, England;Minist Hlth Republ Croatia, Zagreb, Croatia.
    Cardenas, Rosario
    Metropolitan Autonomous Univ, Mexico City, DF, Mexico.
    Carrero, Juan Jesus
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Stockholm, Sweden.
    Carvalho, Felix
    Univ Porto, Fac Pharm, Porto, Portugal.
    Castaneda-Orjuela, Carlos A.
    Inst Nacl Salud, Colombian Natl Hlth Observ, Bogota, Colombia;Univ Nacl Colombia, Publ Hlth Dept, Epidemiol & Publ Hlth Evaluat Grp, Bogota, Colombia.
    Rivas, Jacqueline Castillo
    Univ Costa Rica, San Pedro, Costa Rica;Caja Costarricense Seguro Social, San Jose, Costa Rica.
    Catala-Lopez, Ferran
    Univ Valencia, INCLIVA Hlth Res Inst, Dept Med, Valencia, Spain;Univ Valencia, CIBERSAM, Dept Med, Valencia, Spain;Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada.
    Cercy, Kelly
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Chalek, Julian
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Chang, Hsing-Yi
    Natl Hlth Res Inst, Zgunan Town, Taiwan;Natl Yang Ming Univ, Taipei, Taiwan.
    Chang, Jung-Chen
    Natl Taiwan Univ, Coll Med, Sch Nursing, Taipei, Taiwan.
    Chattopadhyay, Aparajita
    Int Inst Populat Sci, Mumbai, Maharashtra, India.
    Chaturvedi, Pankaj
    Tata Mem Hosp, Mumbai, Maharashtra, India.
    Chiang, Peggy Pei-Chia
    Gold Coast Hlth, Clin Governance Unit, Southport, Qld, Australia.
    Chisumpa, Vesper Hichilombwe
    Univ Zambia, Lusaka, Zambia;Univ Witwatersrand, Johannesburg, South Africa.
    Choi, Jee-Young J.
    Seoul Natl Univ, Seoul, South Korea;Seoul Natl Univ, Med Lib, Seoul, South Korea.
    Christensen, Hanne
    Bispebjerg Hosp, Copenhagen, Denmark.
    Christopher, Devasahayam Jesudas
    Christian Med Coll & Hosp, Vellore, Tamil Nadu, India.
    Chung, Sheng-Chia
    UCL, Inst Hlth Informat, Farr Inst Hlth Informat Res, London, England.
    Ciobanu, Liliana G.
    Univ Adelaide, Sch Med, Discipline Psychiat, Adelaide, SA, Australia.
    Cirillo, Massimo
    Univ Salerno, Baronissi, Italy.
    Colombara, Danny
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Conti, Sara
    Univ Milano Bicocca, Monza, Italy.
    Cooper, Cyrus
    Univ Oxford, NIHR Musculoskeletal Biomed Res Ctr, Oxford, England;Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England.
    Cornaby, Leslie
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Cortesi, Paolo Angelo
    Univ Milano Bicocca, Res Ctr Publ Hlth, Monza, Italy.
    Cortinovis, Monica
    IRCCS, Ist Ric Farmacol Mario Negri, Milan, Italy.
    Pereira, Alexandre Costa
    Univ Sao Paulo, Inst Heart, Sao Paulo, Brazil.
    Cousin, Ewerton
    Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil.
    Criqui, Michael H.
    Univ Calif San Diego, San Diego, CA 92103 USA.
    Cromwell, Elizabeth A.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Crowe, Christopher Stephen
    Univ Washington, Seattle, WA 98195 USA.
    Crump, John A.
    Univ Otago, Dunedin Sch Med, Ctr Int Hlth, Dunedin, New Zealand.
    Daba, Alemneh Kabeta
    Hawassa Univ, Hawassa, Ethiopia.
    Dachew, Berihun Assefa
    Univ Gondar, Inst Publ Hlth, Gondar, Ethiopia;Univ Queensland, Brisbane, Qld, Australia;Wolaita Sodo Univ, Wolaita Sodo, Ethiopia.
    Dadi, Abel Fekadu
    Univ Gondar, Gondar, Ethiopia;Flinders Univ S Australia, Adelaide, SA, Australia.
    Dandona, Lalit
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA;Publ Hlth Fdn India, Gurugram, India.
    Dandona, Rakhi
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA;Publ Hlth Fdn India, Gurugram, India.
    Dargan, Paul I.
    Guys & St Thomas NHS Fdn Trust, London, England.
    Daryani, Ahmad
    Mazandaran Univ Med Sci, Toxoplasmosis Res Ctr, Sari, Iran.
    Daryani, Maryam
    Mazandaran Univ Med Sci, Sari, Iran.
    Das, Jai
    Aga Khan Univ, Dept Paediat & Child Hlth, Karachi, Pakistan.
    Das, Siddharth Kumar
    KG Med Univ, Lucknow, Uttar Pradesh, India.
    das Neves, Jose
    Univ Porto, INEB Inst Engn Biomed, Porto, Portugal;Univ Porto, Inst Invest & Inovacao Sande I3S, Porto, Portugal.
    Weaver, Nicole Davis
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Davletov, Kairat
    Kazakh Natl Med Univ, Sch Publ Hlth, Alma Ata, Kazakhstan.
    de Courten, Barbora
    Monash Univ, Melbourne, Vic, Australia;Monash Med Ctr, Clayton, Vic, Australia.
    De Leo, Diego
    Griffith Univ, Brisbane, Qld, Australia.
    De Neve, Jan-Walter
    Heidelberg Inst Publ Hlth, Heidelberg, Germany.
    Dellavalle, Robert P.
    Univ Colorado, Sch Med, Aurora, CO USA;Colorado Sch Publ Hlth, Aurora, CO USA.
    Demoz, Gebre
    Addis Ababa Univ, Addis Ababa, Ethiopia;Aksum Univ, Aksum, Ethiopia.
    Deribe, Kebede
    Addis Ababa Univ, Sch Publ Hlth, Addis Ababa, Ethiopia;Brighton & Sussex Med Sch, Brighton, E Sussex, England.
    Des Jarlais, Don C.
    Mt Sinai Beth Israel, New York, NY USA;Icahn Sch Med Mt Sinai, New York, NY 10029 USA.
    Dey, Subhojit
    Indian Inst Publ Hlth, Gurugram, India.
    Dharmaratne, Samath D.
    Univ Peradeniya, Fac Med, Dept Community Med, Peradeniya, Sri Lanka.
    Dhimal, Meghnath
    Govt Nepal, Nepal Hlth Res Council, Kathmandu, Nepal.
    Djalalinia, Shirin
    Minist Hlth & Med Educ, Res & Technol, Tehran, Iran.
    Doku, David Teye
    Univ Cape Coast, Cape Coast, Ghana;Univ Tampere, Tampere, Finland.
    Dolan, Kate
    UNSW, Sydney, NSW, Australia.
    Dorsey, E. Ray
    Univ Rochester, Med Ctr, Rochester, NY 14642 USA.
    Bender dos Santos, Kadine Priscila
    Univ Estado Santa Catarina, Florianopolis, SC, Brazil.
    Doyle, Kerrie E.
    Australian Natl Univ, Res Sch Populat Hlth, Dept Global Hlth, Canberra, ACT, Australia;RMIT Univ, Bundoora, Vic, Australia.
    Driscoll, Tim R.
    Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW, Australia.
    Dubey, Manisha
    Int Inst Populat Sci, Mumbai, Maharashtra, India.
    Dubljanin, Eleonora
    Univ Belgrade, Inst Microbiol & Immunol, Belgrade, Serbia.
    Duncan, Bruce Bartholow
    Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil;Univ N Carolina, Chapel Hill, NC 27515 USA.
    Echko, Michelle
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Edessa, Dumessa
    Haramaya Univ, Harar, Ethiopia.
    Edvardsson, David
    La Trobe Univ, Bundoora, Vic, Australia;Umea Univ, Umea, Sweden.
    Ehrlich, Joshua R.
    Univ Michigan, Ann Arbor, MI 48109 USA.
    Eldrenkamp, Erika
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    El-Khatib, Ziad
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden;Harvard Med Sch, Dept Global Hlth & Social Med, Kigali, Rwanda.
    Endres, Matthias
    Charite Univ Med Berlin, Berlin, Germany.
    Endries, Aman Yesuf
    Arba Minch Univ, Arba Minch, Ethiopia.
    Eshrati, Babak
    Minist Hlth & Med Educ, Tehran, Iran;Arak Univ Med Sci, Arak, Iran.
    Eskandarieh, Sharareh
    Multiple Sclerosis Res Ctr, Tehran, Iran.
    Esteghamati, Alireza
    Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Tehran, Iran.
    Fakhar, Mahdi
    Mazandaran Univ Med Sci, Sch Med, Mol & Cell Biol Res Ctr, Sari, Iran.
    Farag, Tamer
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Faramarzi, Mahbobeh
    Babol Univ Med Sci, Babol Sar, Iran.
    Faraon, Emerito Jose Aquino
    Univ Philippines Manila, Coll Publ Hlth, Manila, Philippines;Univ Philippines Manila, Coll Publ Hlth, Dept Hlth Policy & Adm, Manila, Philippines;Dept Hlth, Manila, Philippines.
    Faro, Andre
    Univ Fed Sergipe, Aracaju, Brazil.
    Farzadfar, Farshad
    Univ Tehran Med Sci, Noncommun Dis Res Ctr, Tehran, Iran.
    Fatusi, Adesegun
    Obafemi Awolowo Univ, Coll Hlth Sci, Dept Community Hlth, Ife, Nigeria.
    Fazeli, Mir Sohail
    Doctor Evidence, Santa Monica, CA USA.
    Feigin, Valery L.
    Auckland Univ Technol, Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand.
    Feigl, Andrea B.
    Harvard Univ, Harvard T H Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA.
    Fentahun, Netsanet
    Jimma Univ, Inst Hlth, Fac Publ Hlth, Dept Hlth Behav & Soc, Jimma, Ethiopia.
    Fereshtehnejad, Seyed-Mohammad
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Stockholm, Sweden.
    Fernandes, Eduarda
    Univ Porto, Dept Chem Sci, Porto, Portugal.
    Fernandes, Joao C.
    Catholic Univ Portugal, Fac Biotechnol, CBQF Ctr Biotechnol & Fine Chem Associate Lab, Porto, Portugal.
    Fijabi, Daniel Obadare
    Brandeis Univ, Heller Grad Sch, Waltham, MA USA.
    Filip, Irina
    Kaiser Permanente, Fontana, CA USA.
    Fischer, Florian
    Univ Bielefeld, Sch Publ Hlth, Bielefeld, Germany.
    Fitzmaurice, Christina
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA;Univ Washington, Dept Med, Div Hematol, Seattle, WA 98195 USA;Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA.
    Flaxman, Abraham D.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Flor, Luisa Sorio
    Escola Nacl Sande Publ Sergio Arouca, Rio De Janeiro, Brazil;Univ Fed Espirito Santo, Vitoria, Brazil.
    Foigt, Nataliya
    Acad Med Sci, Inst Gerontol, Kiev, Ukraine. Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland.
    Foreman, Kyle J.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA;Imperial Coll London, London, England.
    Frostad, Joseph J.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Fuerst, Thomas
    Futran, Neal D.
    Univ Washington, Seattle, WA 98195 USA.
    Gakidou, Emmanuela
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Gallus, Silvano
    IRCCS, Ist Ric Farmacol Mario Negri, Milan, Italy;Univ Fed Santa Catarina, Florian6poliss, Brazil.
    Gambashidze, Ketevan
    Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia.
    Gamkrelidze, Amiran
    Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia.
    Ganji, Morsaleh
    Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Tehran, Iran.
    Gebre, Abadi Kahsu
    Mekelle Univ, Mekelle, Ethiopia.
    Gebrehiwot, Tsegaye Tewelde
    Jimma Univ, Jimma, Ethiopia.
    Gebremedhin, Amanuel Tesfay
    Jimma Univ, Jimma, Ethiopia;Ludwig Maximilians Univ Munchen, Munich, Germany.
    Gelaw, Yalemzewod Assefa
    Univ Gondar, Inst Publ Hlth, Gondar, Ethiopia;Univ Queensland, Sch Publ Hlth, Brisbane, Qld, Australia.
    Geleijnse, Johanna M.
    Wageningen Univ, Div Human Nutr, Wageningen, Netherlands.
    Geremew, Demeke
    Univ Gondar, Gondar, Ethiopia.
    Gething, Peter W.
    Univ Oxford, Dept Zool, Oxford, England.
    Ghadimi, Reza
    Babol Univ Med Sci, Hlth Res Inst, Babol Sar, Iran;Dept Nutr, Babol Sar, Iran.
    Falavarjani, Khalil Ghasemi
    Ghasemi-Kasman, Maryam
    Babol Univ Med Sci, Babol Sar, Iran.
    Gill, Paramjit Singh
    Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England.
    Giref, Ababi Zergaw
    Addis Ababa Univ, Addis Ababa, Ethiopia.
    Giroud, Maurice
    Univ Hosp Dijon, Dijon, France.
    Gishu, Melkamu Dedefo
    Haramaya Univ, Harar, Ethiopia;Kersa Hlth & Demog Surveillance Syst, Harar, Ethiopia.
    Giussani, Giorgia
    IRCCS, Ist Ric Farmacol Mario Negri, Milan, Italy.
    Godwin, William W.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Goli, Srinivas
    Jawaharlal Nehru Univ, New Delhi, India.
    Gomez-Dantes, Hector
    Natl Inst Publ Hlth, Cuemavaca, Mexico.
    Gona, Philimon N.
    Univ Massachusetts, Boston, MA 02125 USA.
    Goodridge, Amador
    Inst Invest Cient Serv Alta Tecnol INDICASAT AIP, Ciudad Saber, Panama.
    Gopalani, Sameer Vali
    Govt Federated States Micronesia, Dept Hlth & Social Affairs, Palikir, Micronesia.
    Goryakin, Yevgeniy
    Org Econ Cooperat & Dev, Paris, France.
    Goulart, Alessandra Carvalho
    Univ Sao Paulo, Univ Hosp, Ctr Clin, Sao Paulo, Brazil;Univ Sao Paulo, Univ Hosp, Epidemiol Res Ctr, Sao Paulo, Brazil.
    Grada, Ayman
    Boston Univ, Sch Med, Boston, MA 02215 USA.
    Griswold, Max
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Grosso, Giuseppe
    Univ Hosp Policlin Vittorio Emanuele, Catania, Italy;NNEdPro Global Ctr Nutr & Hlth, Cambridge, England.
    Gugnani, Harish Chander
    St James Sch Med, Dept Microbiol, Quarter, Anguilla;St James Sch Med, Dept Epidemiol & Biostat, Quarter, Anguilla.
    Guo, Yuming
    Univ Queensland, Brisbane, Qld, Australia.
    Gupta, Rahul
    West Virginia Bur Publ Hlth, Charleston, WV USA.
    Gupta, Rajeev
    Eternal Heart Care Ctr, Jaipur, Rajasthan, India;Res Inst, Jaipur, Rajasthan, India.
    Gupta, Tanush
    Montefiore Med Ctr, Bronx, NY 10467 USA;Albert Einstein Coll Med, Bronx, NY 10467 USA.
    Gupta, Tarun
    Indian Inst Technol Kanpur, Kanpur, Uttar Pradesh, India.
    Gupta, Vipin
    Univ Delhi, Dept Anthropol, Delhi, India.
    Haagsma, Juanita A.
    Univ Med Ctr Rotterdam, Erasmus MC, Rotterdam, Netherlands.
    Hachinski, Vladimir
    Western Univ, London, ON, Canada.
    Hafezi-Nejad, Nima
    Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Tehran, Iran.
    Hailu, Gessessew Bugssa
    Mekelle Univ, Mekelle, Ethiopia;Kilte Awlaelo Hlth & Demog Surveillance Syst, Mekelle, Ethiopia.
    Hamadeh, Randah Ribhi
    Arabian Gulf Univ, Manama, Bahrain.
    Hamidi, Samer
    Hamdan Bin Mohammed Smart Univ, Abu Dhabi, U Arab Emirates.
    Hankey, Graeme J.
    Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia;Harry Perkins Inst Med Res, Nedlands, WA, Australia;Western Australian Neurosci Res Inst, Nedlands, WA, Australia.
    Harb, Hilda L.
    Harewood, Heather C.
    Eunice Gibson Polyclin, Bridgetown, Barbados.
    Harikrishnan, Sivadasanpillai
    Sree Chitra Tirunal Inst Med Sci & Technol, Trivandrum, Kerala, India.
    Haro, Josep Maria
    Parc Sanitari St Joan Deu CIBERSAM, Barcelona, Spain.
    Hassen, Hamid Yimam
    Mizan Tepi Univ, Mizan Aman, Ethiopia.
    Havmoeller, Rasmus
    Hawley, Caitlin
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Hay, Simon I.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA;Univ Oxford, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford Big Data Inst, Oxford, England.
    He, Jiawei
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Hearps, Stephen J. C.
    Murdoch Childrens Res Hosp, Child Neuropsychol, Parkville, Vic, Australia.
    Hegazy, Mohamed I.
    Cairo Univ, Fac Med, Cairo, Egypt.
    Heibati, Behzad
    Iran Univ Med Sci, Air Pollut Res Ctr, Tehran, Iran.
    Heidari, Mohsen
    Hormozgan Univ Med Sci, Fac Hlth, Bandar Abbas, Iran.
    Hendrie, Delia
    Curtin Univ, Sch Publ Hlth, Perth, WA, Australia.
    Henry, Nathaniel J.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Herrera Ballesteros, Victor Hugo
    Gorgas Mem Inst Studies Hlth, Panama City, Panama;Univ Panama, Panama City, Panama.
    Herteliu, Claudiu
    Bucharest Univ Econ Studies, Dept Stat & Econometr, Bucharest, Romania.
    Hibstu, Desalegn Tsegaw
    Hawassa Univ, Coll Med & Hlth Sci, Hawassa, Ethiopia.
    Hiluf, Molla Kahssay
    Samara Univ, Samara, Ethiopia.
    Hoek, Hans W.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands;Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10027 USA.
    Rad, Enayatollah Homaie
    Guilan Univ Med Sci, Guilan Rd Trauma Res Ctr, Rasht, Iran.
    Horita, Nobuyuki
    Yokohama City Univ, Grad Sch Med, Dept Pulmonol, Yokohama, Kanagawa, Japan.
    Hosgood, H. Dean
    Albert Einstein Coll Med, Bronx, NY 10467 USA.
    Hosseini, Mostafa
    Hosseini, Seyed Reza
    Babol Univ Med Sci, Social Determinants Hlth Res Ctr, Hlth Res Inst, Babol Sar, Iran.
    Hostiuc, Mihaela
    Carol Davila Univ Med & Pharm, Bucharest, Romania.
    Hostiuc, Sorin
    Carol Davila Univ Med & Pharm, Bucharest, Romania.
    Hoy, Damian G.
    Pacific Community, Publ Hlth Div, Noumea, New Caledonia.
    Hsairi, Mohamed
    Salah Azaiz Inst, Dept Epidemiol, Tunis, Tunisia.
    Htet, Aung Soe
    Univ Oslo, Oslo, Norway.
    Hu, Guoqing
    Cent S Univ, Sch Publ Hlth, Dept Epidemiol & Hlth Stat, Changsha, Peoples R China.
    Huang, John J.
    Yale Univ, New Haven, CT USA.
    Iburg, Kim Moesgaard
    Aarhus Univ, Aarhus, Denmark.
    Idris, Fachmi
    Sriwijaya Univ, Palembang, Indonesia;Social Secur Administering Body Hlth, Jakarta, Indonesia.
    Igumbor, Ehimario Uche
    US Ctr Dis Control & Prevent, Pretoria, South Africa;Univ Western Cape, Sch Publ Hlth, Cape Town, South Africa.
    Ikeda, Chad
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Ileanu, Bogdan Vasile
    Bucharest Univ Econ Studies, Bucharest, Romania.
    Ilesanmi, Olayinka S.
    Natl Publ Hlth Inst, Monrovia, CA, Liberia.
    Innos, Kaire
    Natl Inst Hlth Dev, Tallinn, Estonia.
    Irvani, Seyed Sina Naghibi
    Prevent Metab Disorders Res Ctr, Res Inst Endocrine Sci, Tehran, Iran;Shahid Beheshti Univ Med Sci, Tehran, Iran.
    Irvine, Caleb M. S.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Islami, Farhad
    Amer Canc Soc, Surveillance & Hlth Serv Res, Atlanta, GA 30329 USA.
    Jacobs, Troy A.
    USAID Global Hlth Bur, HIDN, MCH Div, Washington, DC USA.
    Jacobsen, Kathryn H.
    George Mason Univ, Dept Global & Community Hlth, Fairfax, VA 22030 USA.
    Jahanmehr, Nader
    Shahid Beheshti Univ Med Sci, Sch Publ Hlth, Tehran, Iran.
    Jain, Rajesh
    Jain Hosp MSS, Kanpur, Uttar Pradesh, India.
    Jain, Sudhir Kumar
    Natl Ctr Dis Control Delhi, Delhi, India.
    Jakovljevic, Mihajlo M.
    Univ Washington, Ctr Hlth Trends & Forecasts, Seattle, WA 98195 USA;Univ Kragujevac, Fac Med Sci, Kragujevac, Serbia.
    Jalu, Moti Tolera
    Haramaya Univ, Harar, Ethiopia;St Pauls Hosp, Millennium Med Coll, Addis Ababa, Ethiopia.
    Jamal, Amr A.
    Javanbakht, Mehdi
    Univ Aberdeen, Aberdeen, Scotland.
    Jayatilleke, Achala Upendra
    Postgrad Inst Med, Colombo, Sri Lanka;Inst Violence & Injury Prevent, Colombo, Sri Lanka.
    Jeemon, Panniyammakal
    Ctr Control Chron Condit, Gurugram, India;Ctr Chron Dis Control, New Delhi, India.
    Jha, Ravi Prakash
    Banaras Hindu Univ, Varanasi, Uttar Pradesh, India.
    Jha, Vivekanand
    Univ Oxford, Oxford, England;George Inst Global Hlth, New Delhi, India.
    Jozwiak, Jacek
    Czestochowa Tech Univ, Inst Hlth & Nutr Sci, Czestochowa, Poland.
    John, Oommen
    George Inst Global Hlth, New Delhi, India.
    Johnson, Sarah Charlotte
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Jonas, Jost B.
    Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany.
    Joshua, Vasna
    Indian Council Med Res, Natl Inst Epidemiol, Chennai, Tamil Nadu, India.
    Juerisson, Mikk
    Univ Tartu, Inst Family Med & Publ Hlth, Tartu, Estonia.
    Kabir, Zubair
    Univ Coll Cork, Cork, Ireland.
    Kadel, Rajendra
    London Sch Econ & Polit Sci, London, England.
    Kahsay, Amaha
    Mekelle Univ, Mekelle, Ethiopia.
    Kalani, Rizwan
    Univ Washington, Seattle, WA 98195 USA.
    Kar, Chittaranjan
    SCB Med Coll, Cuttack, Orissa, India.
    Karanikolos, Marina
    European Observ Hlth Syst & Policies, London, England.
    Karch, Andre
    Helmholtz Ctr Infect Res, Epidemiol & Stat Methods Res Grp, Braunschweig, Germany;German Ctr Infect Res, Hannover, Germany.
    Karema, Corine Kakizi
    Swiss Trop & Publ Hlth Inst, Basel, Switzerland. Univ Basel, Basel, Switzerland;Qual & Equity Hlth Care, Kigali, Rwanda.
    Karimi, Seyed M.
    Univ Washington Tacoma, Tacoma, WA USA.
    Kasaeian, Amir
    Univ Tehran Med Sci, Hematol Malignancies Res Ctr, Tehran, Iran;Univ Tehran Med Sci, Hematol Oncol & Stem Cell Transplantat Res Ctr, Tehran, Iran.
    Kassa, Dessalegn Haile
    Debre Markos Univ, Debre Markos, Ethiopia.
    Kassa, Getachew Mullu
    Debre Markos Univ, Debre Markos, Ethiopia.
    Kassa, Tesfaye Dessale
    Mekelle Univ, Mekelle, Ethiopia.
    Kassebaum, Nicholas J.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA;Seattle Childrens Hosp, Dept Anesthesiol & Pain Med, Seattle, WA USA.
    Katikireddi, Srinivasa Vittal
    Univ Glasgow, MRC CSO Social Publ Hlth Sci Unit, Glasgow, Lanark, Scotland.
    Kaul, Anil
    Oklahoma State Univ, Tulsa, OK USA.
    Kawakami, Norito
    Univ Tokyo, Sch Publ Hlth, Tokyo, Japan.
    Kazanjan, Konstantin
    Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia.
    Kebede, Seifu
    Mekelle Univ, Mekelle, Ethiopia.
    Keiyoro, Peter Njenga
    Inst Trop & Infect Dis, Nairobi, Kenya;Sch Continuing & Distance Educ, Nairobi, Kenya.
    Kemp, Grant Rodgers
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Kengne, Andre Pascal
    South African Med Res Council, UKZN Gastrointestinal Canc Res Ctr, Cape Town, South Africa;Univ Cape Town, Fac Hlth Sci, Hatter Inst Cardiovasc Res Africa, Dept Psychiat, Cape Town, South Africa.
    Kereselidze, Maia
    Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia.
    Ketema, Ezra Belay
    Mekelle Univ, Mekelle, Ethiopia.
    Khader, Yousef Saleh
    Jordan Univ Sci & Technol, Dept Community Med Publ Hlth & Family Med, Irbid, Jordan;Jordan Univ Sci & Technol, Fac Appl Med Sci, Dept Rehabil Sci, Div Phys Therapy, Irbid, Jordan.
    Khafaie, Morteza Abdullatif
    Ahvaz Jundishapur Univ Med Sci, Ahwaz, Iran.
    Khajavi, Alireza
    Shahid Beheshti Univ Med Sci, Tehran, Iran.
    Khalil, Ibrahim A.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Khan, Ejaz Ahmad
    Hlth Serv Acad, Islamabad, Pakistan.
    Khan, Gulfaraz
    United Arab Emirates Univ, Coll Med Hlth Sci, Dept Microbiol & Immunol, Al Ain, U Arab Emirates.
    Khan, Md Nuruzzaman
    Univ Newcastle, Newcastle, NSW, Australia;Jatiya Kabi Kazi Nazrul Islam Univ, Mymensingh, Bangladesh.
    Khan, Muhammad Ali
    Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA;Univ Tennessee, Hlth Sci Ctr, Memphis, TN 38163 USA.
    Khanal, Mukti Nath
    Dept Hlth Serv Hlth Management Informat Syst, Kathmandu, Nepal.
    Khang, Young-Ho
    Seoul Natl Univ, Dept Hlth Policy & Management, Coll Hlth Sci, Seoul, South Korea;Seoul Natl Univ, Med Ctr, Inst Hlth Policy & Management, Seoul, South Korea.
    Khater, Mona M.
    Cairo Univ, Fac Med, Cairo, Egypt;Cairo Univ, Cairo, Egypt.
    Khoja, Abdullah Tawfih Abdullah
    Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Clin Global Hlth Educ, Baltimore, MD USA;Mohammed Ibn Saudi Univ, Coll Med, Dept Publ Hlth, Riyadh, Saudi Arabia;Mohammed Ibn Saudi Univ, Coll Med, Dept Family Med, Riyadh, Saudi Arabia.
    Khosravi, Ardeshir
    Univ Tehran Med Sci, Noncommun Dis Res Ctr, Tehran, Iran;Iranian Minist Hlth & Med Educ, Tehran, Iran.
    Khubchandani, Jagdish
    Ball State Univ, Dept Nutr & Hlth Sci, Muncie, IN 47306 USA.
    Kibret, Getiye Dejenu
    Addis Ababa Univ, Coll Vet Med & Agr, Addis Ababa, Ethiopia;Debre Markos Univ, Debre Markos, Ethiopia.
    Kiirithio, Daniel Ngari
    Kenya Revenue Author, Nairobi, Kenya;Synotech Consultants, Nairobi, Kenya.
    Kim, Daniel
    Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA.
    Kim, Yun Jin
    Xiamen Univ, Sch Med, Malaysia Campus, Sepang, Malaysia.
    Kimokoti, Ruth W.
    Simmons Coll, Boston, MA 02115 USA.
    Kinfu, Yohannes
    Univ Canberra, Ctr Res & Action Publ Hlth, Canberra, ACT, Australia.
    Kinra, Sanjay
    London Sch Hyg & Trop Med, London, England.
    Kisa, Adnan
    Univ Oslo, Oslo, Norway.
    Kissoon, Niranjan
    Univ British Columbia, Fac Med, Sch Populat & Publ Hlth, Vancouver, BC, Canada.
    Kochhar, Sonali
    Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA;Global Healthcare Consulting, New Delhi, India.
    Kokubo, Yoshihiro
    Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan.
    Kopec, Jacek A.
    Univ British Columbia, Fac Med, Sch Populat & Publ Hlth, Vancouver, BC, Canada.
    Kosen, Soewarta
    Natl Inst Hlth Res Dev, Ctr Community Empowerment Hlth Policy & Humanitie, Jakarta, Indonesia.
    Koul, Parvaiz A.
    Sher Kashmir Inst Med Sci, Srinagar, Jammu & Kashmir, India.
    Koyanagi, Ai
    Parc Sanitari St Joan Deu CIBERSAM, Res & Dev Unit, Barcelona, Spain.
    Kravchenko, Michael
    Res Ctr Neurol, Moscow, Russia.
    Krishan, Kewal
    Panjab Univ, Chandigarh, India.
    Krohn, Kristopher J.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Defo, Barthelemy Kuate
    Univ Montreal, Sch Publ Hlth, Dept Demog, Montreal, PQ, Canada;Univ Montreal, Sch Publ Hlth, Publ Hlth Res Inst, Montreal, PQ, Canada;Univ Montreal, Sch Publ Hlth, Dept Social & Prevent Med, Montreal, PQ, Canada.
    Kumar, G. Anil
    Publ Hlth Fdn India, Gurugram, India.
    Kumar, Pushpendra
    Int Inst Populat Sci, Mumbai, Maharashtra, India.
    Kutz, Michael
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Kuzin, Igor
    Minist Hlth Ukraine, State Inst Publ Hlth Ctr, Kiev, Ukraine.
    Kyu, Hmwe H.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Lad, Deepesh Pravinkumar
    Postgrad Inst Med Educ & Res, Chandigarh, India.
    Lafranconi, Alessandra
    Univ Milano Bicocca, Monza, Italy.
    Lal, Dharmesh Kumar
    Publ Hlth Fdn India, Gurugram, India.
    Lalloo, Ratilal
    Univ Queensland, Sch Dent, Brisbane, Qld, Australia.
    Lam, Hilton
    NHLBI, Ctr Translat Res & Implementat Sci, Inst Hlth Policy & Dev Studies, Natl Inst Hlth, Manila, Philippines.
    Lan, Qing
    NCI, Rockville, MD USA.
    Lang, Justin J.
    Publ Hlth Agcy Canada, Toronto, ON, Canada;Childrens Hosp, Eastern Ontario Res Inst, Ottawa, ON, Canada.
    Lansingh, Van C.
    Help Me See Inc, New York, NY USA;Inst Mexicano Oftalmol, Queretaro, Mexico.
    Lansky, Sonia
    Univ Fed Minas Gerais, Sch Med, Belo Horizonte, MG, Brazil;Secretaria Municipal Sande, Belo Horizonte, MG, Brazil.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Latifi, Arman
    Maragheh Univ Med Sci, Managerial Epidemiol Res Ctr, Sch Nursing & Midwifery, Dept Publ Hlth, Maragheh, Iran.
    Lazarus, Jeffrey Victor
    Univ Barcelona, Hosp Clin, ISGlobal, Barcelona, Spain;Univ Copenhagen, Rigshosp, CHIP, Copenhagen, Denmark.
    Leasher, Janet L.
    Nova Southeastern Univ, Coll Optometry, Ft Lauderdale, FL 33314 USA.
    Lee, Paul H.
    Hong Kong Polytech Univ, Hong Kong, Hong Kong, Peoples R China.
    Legesse, Yirga
    Mekelle Univ, Mekelle, Ethiopia.
    Leigh, James
    Univ Sydney, Sydney, NSW, Australia.
    Leshargie, Cheru Tesema
    Debre Markos Univ, Debre Markos, Ethiopia.
    Leta, Samson
    Addis Ababa Univ, Addis Ababa, Ethiopia.
    Leung, Janni
    Univ Washington, Seattle, WA 98195 USA;Univ Queensland, Sch Publ Hlth, Brisbane, Qld, Australia.
    Leung, Ricky
    SUNY Albany, Albany, NY 12222 USA.
    Levi, Miriam
    Tuscany Reg Ctr Occupat Injuries & Dis, Florence, Italy.
    Li, Yongmei
    San Francisco VA Med Ctr, San Francisco, CA USA.
    Liang, Juan
    Sichuan Univ, West China Univ Hosp 2, Natl Off Maternal & Child Hlth Surveillance, Chengdu, Sichuan, Peoples R China.
    Liben, Misgan Legesse
    Samara Univ, Samara, Ethiopia.
    Lim, Lee-Ling
    Univ Malaya, Kuala Lumpur, Malaysia;Chinese Univ Hong Kong, Shatin, Hong Kong, Peoples R China.
    Lim, Stephen S.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Lind, Margaret
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Linn, Shai
    Univ Haifa, Haifa, Israel.
    Listl, Stefan
    Heidelberg Univ, Heidelberg, Germany;Radboud Univ Nijmegen Med Ctr, Nijmegen, Netherlands.
    Liu, Patrick Y.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Liu, Shiwei
    Chinese Ctr Dis Control & Prevent, Natl Ctr Chron & Noncommunicable Dis Control & Pr, Beijing, Peoples R China.
    Lodha, Rakesh
    All India Inst Med Sci, New Delhi, India.
    Lopez, Alan D.
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Melbourne, Vic 3010, Australia.
    Lorch, Scott A.
    Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA.
    Lorkowski, Stefan
    Friedrich Schiller Univ Jena, Inst Nutr, Jena, Germany;Competence Cluster Nutr & Cardiovasc Hlth NutriCA, Jena, Germany.
    Lotufo, Paulo A.
    Univ Sao Paulo, Sao Paulo, Brazil.
    Lucas, Timothy C. D.
    Univ Oxford, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford Big Data Inst, Oxford, England;Univ Oxford, Nuffield Dept Med, Oxford, England.
    Lunevicius, Raimundas
    Aintree Univ Hosp Natl Hlth Serv Fdn Trust, Liverpool, Merseyside, England;Univ Liverpool, Sch Med, Liverpool, Merseyside, England.
    Lurton, Gregoire
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Lyons, Ronan A.
    Swansea Univ, Farr Inst, Swansea, W Glam, Wales.
    Maalouf, Fadi
    Amer Univ Beirut, Fac Hlth Sci, Ctr Res Populat & Hlth, Dept Psychiat, Beirut, Lebanon.
    Macarayan, Erlyn Rachelle King
    Harvard Univ, Ariadne Labs, Boston, MA 02115 USA.
    Mackay, Mark T.
    Univ Melbourne, Melbourne, Vic 3010, Australia;Royal Childrens Hosp Melbourne, Melbourne, Vic, Australia.
    Maddison, Emilie R.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Madotto, Fabiana
    Univ Milano Bicocca, Monza, Italy.
    Abd El Razek, Hassan Magdy
    Mansoura Fac Med, Mansoura, Egypt;Aswan Univ Hosp, Aswan Fac Med, Aswan, Egypt.
    Abd El Razek, Mohammed Magdy
    Majdan, Marek
    Trnava Univ, Fac Hlth Sci & Social Work, Dept Publ Hlth, Trnava, Slovakia.
    Majdzadeh, Reza
    Univ Tehran Med Sci, Knowledge Utilizat Res Ctr, Tehran, Iran;Univ Tehran Med Sci, Community Based Participatory Res Ctr, Tehran, Iran;Natl Inst Hlth Res, Tehran, Iran.
    Majeed, Azeem
    Imperial Coll London, Dept Primary Care & Publ Hlth, London, England.
    Malekzadeh, Reza
    Univ Tehran Med Sci, Digest Dis Res Inst, Tehran, Iran.
    Malhotra, Rajesh
    All India Inst Med Sci, New Delhi, India.
    Malta, Deborah Carvalho
    Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil.
    Mamun, Abdullah A.
    Univ Queensland, Brisbane, Qld, Australia.
    Manguerra, Helena
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Manhertz, Treh
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Mansournia, Mohammad Ali
    Univ Tehran Med Sci, Dept Epidemiol & Biostat, Tehran, Iran.
    Mantovani, Lorenzo G.
    Univ Milano Bicocca, Monza, Italy.
    Manyazewal, Tsegahun
    Ethiopian Publ Hlth Assoc, Addis Ababa, Ethiopia.
    Mapoma, Chabila C.
    Univ Zambia, Lusaka, Zambia.
    Margono, Christopher
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Martinez-Raga, Jose
    Hosp Univ Doctor Peset, Valencia, Spain;CEU Cardinal Herrera Univ, Moncada, Spain.
    Martins, Sheila Cristina Ouriques
    Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil;Hosp Moinhos Vento, Porto Alegre, RS, Brazil.
    Martins-Melo, Francisco Rogerlandio
    Fed Inst Educ Sci & Technol Ceara, Caucaia, Brazil. Synlab Acad, Mannheim, Germany. Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria.
    Martopullo, Ira
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Maerz, Winfried
    Massenburg, Benjamin Ballard
    Univ Washington, Dept Surg, Div Plast Surg, Seattle, WA 98195 USA;Harvard Med Sch, Program Global Surg & Social Change, Kigali, Rwanda.
    Mathur, Manu Raj
    Publ Hlth Fdn India, Gurugram, India;UCL, London, England.
    Maulik, Pallab K.
    George Inst Global Hlth India, New Delhi, India;Univ Oxford, George Inst Global Hlth, Oxford, England.
    Mazidi, Mohsen
    Chalmers Univ Technol, Dept Biol & Biol Engn Food & Nutr Sci, Gothenburg, Sweden.
    McAlinden, Colm
    Univ Hosp Bristol NHS Fdn Trust, Bristol, Avon, England;Publ Hlth Wales, Swansea, W Glam, Wales.
    McGrath, John J.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia;Aarhus Univ, Aarhus Sch Business & Social Sci, Natl Ctr Register Based Res, Aarhus, Denmark;Queensland Ctr Mental Hlth Res, Pk Ctr Mental Hlth, Wacol, Qld, Australia.
    McKee, Martin
    London Sch Hyg & Trop Med, London, England.
    Mehata, Suresh
    Ipas Nepal, Kathmandu, Nepal.
    Mehrotra, Ravi
    Natl Inst Canc Prevent Res, Noida, India.
    Mehta, Kala M.
    Univ Calif San Francisco, San Francisco, CA 94143 USA.
    Mehta, Varshil
    MGM Med Coll, Navi Mumbai, India.
    Meier, Toni
    Martin Luther Univ Halle Wittenberg, Inst Medizin Epidemiol Biometrie & Informat, Competence Cluster Nutr & Cardiovasc Hlth NutriCA, Saale, Germany.
    Mejia-Rodriguez, Fabiola
    Natl Inst Publ Hlth, Cuemavaca, Mexico.
    Meles, Kidanu Gebremariam
    Mekelle Univ, Coll Hlth Sci, Mekelle, Ethiopia;Mekelle Univ, Sch Publ Hlth, Mekelle, Ethiopia.
    Melku, Mulugeta
    Univ Gondar, Gondar, Ethiopia.
    Memiah, Peter
    Univ West Florida, Pensacola, FL 32514 USA.
    Memish, Ziad A.
    Saudi Minist Hlth, Riyadh, Saudi Arabia;Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia.
    Mendoza, Walter
    United Nations Populat Fund, Lima, Peru.
    Mengiste, Degu Abate
    Haramaya Univ, Harar, Ethiopia.
    Mengistu, Desalegn Tadese
    Mekelle Univ, Coll Hlth Sci, Mekelle, Ethiopia.
    Menota, Bereket Gebremichael
    Addis Ababa Univ, Addis Ababa, Ethiopia.
    Mensah, George A.
    NHLBI, Ctr Translat Res & Implementat Sci, Inst Hlth Policy & Dev Studies, Natl Inst Hlth, Manila, Philippines.
    Meretoja, Atte
    Univ Melbourne, Dept Med, Melbourne, Vic, Australia;Helsinki Univ Hosp, Comprehens Canc Ctr, Dept Neurol, Breast Surg Unit, Helsinki, Finland.
    Meretoja, Tuomo J.
    Univ Helsinki, Fac Med, Finnish Inst Occupat Hlth, Dept Publ Hlth,Work Org,Work Disability Program, Helsinki, Finland.
    Mezgebe, Haftay Berhane
    Mekelle Univ, Mekelle, Ethiopia.
    Miazgowski, Tomasz
    Pomeranian Med Univ, Szczecin, Poland.
    Micha, Renata
    Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA.
    Milam, Robert
    Doctor Evidence, Santa Monica, CA USA.
    Millear, Anoushka
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Miller, Ted R.
    Curtin Univ, Sch Publ Hlth, Perth, WA, Australia;Pacific Inst Res Evaluat, Calverton, MD USA.
    Mini, G. K.
    Sree Chitra Tirunal Inst Med Sci & Technol, Thiruvananthapuram, Kerala, India;Amrita Inst Med Sci, Kochi, India.
    Minnig, Shawn
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Mirica, Andreea
    Bucharest Univ Econ Studies, Bucharest, Romania.
    Mirrakhimov, Erkin M.
    Kyrgyz State Med Acad, Bishkek, Kyrgyzstan;Natl Ctr Cardiol & Internal Dis, Bishkek, Kyrgyzstan.
    Misganaw, Awoke
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Mitchell, Philip B.
    Univ New South Wales, Sch Optometry & Vision Sci, Brien Holden Vision Inst, Kensington, NSW, Australia.
    Mlashu, Fitsum Weldegebreal
    Haramaya Univ, Harar, Ethiopia.
    Moazen, Babak
    Univ Tehran Med Sci, Noncommun Dis Res Ctr, Endocrinol & Metab Res Inst, Tehran, Iran;Heidelberg Univ, Fac Med Mannheim, Inst Publ Hlth, Dept Ophthalmol, Heidelberg, Germany.
    Mohammad, Karzan Abdulmuhsin
    Salahaddin Univ, Erbil, Iraq;Ishik Univ, Erbil, Iraq.
    Mohammadibakhsh, Roghayeh
    Hamedan Univ Med Sci, Hamadan, Iran.
    Mohammed, Ebrahim
    Mekelle Univ, Mekelle, Ethiopia.
    Mohammed, Mohammed A.
    Jigjiga Univ, Jigjiga, Ethiopia;Univ Sydney, Sydney, NSW, Australia.
    Mohammed, Shafiu
    Heidelberg Univ, Inst Publ Hlth, Heidelberg, Germany;Ahmadu Bello Univ, Hlth Syst & Policy Res Unit, Zaria, Nigeria.
    Mokdad, Ali H.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Mola, Glen Liddell D.
    Univ Papua New Guinea, Sch Med & Hlth Sci, Reprod Hlth & ObGyn, Boroko, Papua N Guinea.
    Molokhia, Mariam
    Kings Coll London, London, England.
    Momeniha, Fatemeh
    Iran Univ Med Sci, Sch Publ Hlth, Dept Environm Hlth Engn, Tehran, Iran.
    Monasta, Lorenzo
    IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy.
    Montanez Hernandez, Julio Cesar
    Natl Inst Publ Hlth, Cuemavaca, Mexico.
    Moosazadeh, Mahmood
    Mazandaran Univ Med Sci, Hlth Sci Res Ctr, Addict Inst, Sari, Iran.
    Moradi-Lakeh, Maziar
    Iran Univ Med Sci, Dept Community Med, Tehran, Iran;Iran Univ Med Sci, Prevent Med & Publ Hlth Res Ctr, Tehran, Iran;Iran Univ Med Sci, Gastrointestinal & Liver Dis Res Ctr, Tehran, Iran.
    Moraga, Paula
    Univ Lancaster, Lancaster Med Sch, Lancaster, England.
    Morawska, Lidia
    Queensland Univ Technol, Int Lab Air Qual & Hlth, Brisbane, Qld, Australia.
    Velasquez, Ilais Moreno
    Gorgas Mem Inst Hlth Studies, Panama City, Panama.
    Mori, Rintaro
    Natl Ctr Child Hlth & Dev, Tokyo, Japan.
    Morrison, Shane D.
    Univ Washington, Seattle, WA 98195 USA.
    Moses, Mark
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Mousavi, Seyyed Meysam
    Univ Tehran Med Sci, Sch Publ Hlth, Dept Hlth Management & Econ, Tehran, Iran.
    Mueller, Ulrich O.
    Fed Inst Populat Res, Competence Ctr Mortal Follow Up German Natl Cohor, Wiesbaden, Germany.
    Murhekar, Manoj
    ICMR Natl Inst Epidemiol, Chennai, Tamil Nadu, India.
    Murthy, Gudlavalleti Venkata Satyanarayana
    London Sch Hyg & Trop Med, London, England.
    Murthy, Srinivas
    Univ British Columbia, Fac Med, Sch Populat & Publ Hlth, Vancouver, BC, Canada.
    Musa, Jonah
    Univ Jos, Jos, Nigeria;Jos Univ, Teaching Hosp, Jos, Nigeria.
    Musa, Kamarul Imran
    Univ Sci Malaysia, Sch Med Sci, Kubang Kerian, Malaysia.
    Mustafa, Ghulam
    Helping Hands Fdn, Multan, Pakistan;Nishtar Med Univ, Multan, Pakistan.
    Muthupandian, Saravanan
    Mekelle Univ, Coll Hlth Sci, Mekelle, Ethiopia;Mekelle Univ, Inst Biomed Sci, Mekelle, Ethiopia;Mekelle Univ, Dept Med Microbiol, Mekelle, Ethiopia.
    Nagata, Chie
    Natl Ctr Child Hlth & Dev, Tokyo, Japan.
    Nagel, Gabriele
    Ulm Univ, Inst Epidemiol & Med Biometry, Ulm, Germany.
    Naghavi, Mohsen
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Naheed, Aliya
    Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh.
    Naik, Gurudatta A.
    Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA.
    Naik, Nitish
    All India Inst Med Sci, New Delhi, India.
    Najafi, Farid
    Kermanshah Univ Med Sci, Sch Publ Hlth, Res Ctr Environm Determinants Hlth, Kermanshah, Iran.
    Naldi, Luigi
    Azienda Osped Papa Giovanni XXIII, Bergamo, Italy.
    Nangia, Vinay
    Suraj Eye Inst, Nagpur, Maharashtra, India.
    Nansseu, Jobert Richie Njingang
    Univ Yaounde, Fac Med & Biomed Sci, Dept Publ Hlth, Yaounde, Cameroon;Minist Publ Hlth, Dept Control Dis Epidem & Pandem, Yaounde, Cameroon.
    Narayan, K. M. Venkat
    Emory Univ, Atlanta, GA 30322 USA.
    Nascimento, Bruno Ramos
    Hosp Univ Ciencias Med, Belo Horizonte, MG, Brazil.
    Negoi, Ionut
    Carol Davila Univ Med & Pharm, Bucharest, Romania;Emergency Hosp Bucharest, Bucharest, Romania.
    Negoi, Ruxandra Irina
    Carol Davila Univ Med & Pharm, Bucharest, Romania.
    Newton, Charles R.
    Univ Oxford, Oxford, England;KEMRI Wellcome Trust, Kilifi, Kenya.
    Ngunjiri, Josephine Wanjiku
    Univ Nairobi, Nairobi, Kenya.
    Nguyen, Grant
    Nguyen, Long
    Nguyen, Trang Huyen
    Nichols, Emma
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Ningrum, Dina Nur Anggraini
    Semarang State Univ, Dept Publ Hlth, Semarang City, Indonesia;Taipei Med Univ, Grad Inst Biomed Informat, Taipei, Taiwan.
    Nolte, Ellen
    London Sch Hyg & Trop Med, European Observ Hlth Syst & Policies, London, England.
    Nong, Vuong Minh
    Norheim, Ole F.
    Univ Bergen, Bergen, Norway.
    Norrving, Bo
    Noubiap, Jean Jacques N.
    Univ Cape Town, Fac Hlth Sci, Hatter Inst Cardiovasc Res Africa, Dept Psychiat, Cape Town, South Africa;Med Diagnost Ctr, Yaounde, Cameroon.
    Nyandwi, Alypio
    Rwanda Minist Hlth, Kigali, Rwanda.
    Obermeyer, Carla Makhlouf
    Amer Univ Beirut, Fac Hlth Sci, Ctr Res Populat & Hlth, Dept Psychiat, Beirut, Lebanon.
    Ofori-Asenso, Richard
    Monash Univ, Melbourne, Vic, Australia.
    Ogbo, Felix Akpojene
    Oh, In-Hwan
    Kyung Hee Univ, Sch Med, Dept Prevent Med, Seoul, South Korea.
    Oladimeji, Olanrewaju
    South Africa & Univ KwaZulu Natal, Human Sci Res Council, Durban, South Africa.
    Olagunju, Andrew Toyin
    Univ Adelaide, Sch Med, Discipline Psychiat, Adelaide, SA, Australia;Univ Lagos, Coll Med, Dept Psychiat, Lagos, Nigeria;Lagos Univ, Teaching Hosp, Dept Psychiat, Lagos, Nigeria.
    Olagunju, Tinuke Oluwasefunmi
    McMaster Univ, Hamilton, ON, Canada;Western Univ, London, ON, Canada.
    Olivares, Pedro R.
    Univ Autonoma Chile, Talca, Chile.
    Vasconcelos de Oliveira, Patricia Pereira
    Minist Hlth Brazil, Brasilia, DF, Brazil.
    Olsen, Helen E.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Olusanya, Bolajoko Olubukunola
    Ctr Healthy Start Initiat, Lagos, Nigeria.
    Olusanya, Jacob Olusegun
    Ctr Healthy Start Initiat, Lagos, Nigeria.
    Ong, Kanyin
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Opio, John Nelson
    Lira Municipal Council, Lira Dist Local Govt, Kampala, Uganda.
    Oren, Eyal
    San Diego State Univ, Grad Sch Publ Hlth, Div Epidemiol & Biostat, San Diego, CA 92182 USA.
    Ortega-Altamirano, Doris V.
    Natl Inst Publ Hlth, Cuemavaca, Mexico.
    Ortiz, Alberto
    UAM, IIS Fdn Jimenez Diaz, Madrid, Spain.
    Ozdemir, Raziye
    Karabuk Univ, Karabuk, Turkey. JSS Univ, JSS Med Coll, Mysore, Karnataka, India.
    Mahesh, P. A.
    Pain, Amanda W.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Palone, Marcos Roberto Tovani
    Univ Sao Paulo, Sao Paulo, Brazil.
    Pana, Adrian
    Bucharest Univ Econ Studies, Bucharest, Romania.
    Panda-Jonas, Songhomitra
    Heidelberg Univ, Fac Med Mannheim, Inst Publ Hlth, Dept Ophthalmol, Heidelberg, Germany.
    Pandian, Jeyaraj D.
    Christian Med Coll Ludhiana, Ludhiana, Punjab, India.
    Park, Eun-Kee
    Kosin Univ, Coll Med, Dept Med Humanities & Social Med, Busan, South Korea.
    Parsian, Hadi
    Babol Univ Med Sci, Babol Sar, Iran.
    Patel, Tejas
    White Plains Hosp, White Plains, NY USA.
    Pati, Sanghamitra
    Publ Hlth Fdn India, Gurugram, India.
    Patil, Snehal T.
    Deemed Univ, Krishan Inst Med Sci, Sch Dent Sci, Karad, India.
    Patle, Ajay
    Minist Hlth Family Welf, Natl Hlth Syst Resource Ctr, New Delhi, India.
    Patton, George C.
    Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia;Univ Melbourne, Murdoch Childrens Res Inst, Melbourne, Vic, Australia.
    Paturi, Vishnupriya Rao
    Diabet Res Soc, Clin Res, Hyderabad, India;DiabetOmics, Portland, OR USA.
    Paudel, Deepak
    UK Dept Int Dev, Lalitpur, Nepal.
    Pedroso, Marcel de Moares
    Fundacao Oswaldo Cruz, Inst Comunicacao & Informacao Cientif & Tecnol Sa, Rio De Janeiro, Brazil.
    Pedroza, Sandra P.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Pereira, David M.
    Univ Porto, Fac Farm, Dept Quim, REQUIMTE,LAQV,Lab Farmacognosia, Porto, Portugal.
    Perico, Norberto
    IRCCS, Ist Ric Farmacol Mario Negri, Milan, Italy.
    Peterson, Hannah
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Petzold, Max
    Univ Witwatersrand, Johannesburg, South Africa;Univ Gothenburg, Hlth Metr Unit, Gothenburg, Sweden.
    Peykari, Niloofar
    Minist Hlth & Med Educ, Tehran, Iran.
    Phillips, Michael Robert
    Emory Univ, Atlanta, GA 30322 USA;Shanghai Jiao Tong Univ, Sch Med, Shanghai, Peoples R China.
    Piel, Frederic B.
    Imperial Coll London, Dept Epidemiol & Biostat, London, England. Imperial Coll London, Dept Infect Dis Epidemiol, London, England.
    Pigott, David M.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Pillay, Julian David
    Durban Univ Technol, Durban, South Africa.
    Piradov, Michael A.
    Res Ctr Neurol, Moscow, Russia.
    Polinder, Suzanne
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands.
    Pond, Constance D.
    Univ Newcastle, Callaghan, NSW, Australia.
    Postma, Maarten J.
    Univ Groningen, Groningen, Netherlands;Univ Med Ctr Groningen, Groningen, Netherlands.
    Pourmalek, Farshad
    Univ British Columbia, Fac Med, Sch Populat & Publ Hlth, Vancouver, BC, Canada.
    Prakash, Swayam
    Sanjay Gandhi Postgrad Inst Med Sci, Lucknow, Uttar Pradesh, India.
    Prakash, V.
    Charotar Univ Sci & Technol, Anand, Gujarat, India.
    Prasad, Narayan
    Sanjay Gandhi Post Grad Inst Med Sci, Lucknow, Uttar Pradesh, India.
    Prasad, Noela Marie
    Univ Melbourne, Melbourne, Vic 3010, Australia;Fred Hollows Fdn, Melbourne, Vic, Australia.
    Purcell, Caroline
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Qorbani, Mostafa
    Alborz Univ Med Sci, Noncommunicable Dis Res Ctr, Karaj, Iran.
    Quintana, Hedley Knewjen
    Commemorat Gorgas Inst Hlth Studies, Panama City, Panama.
    Radfar, Amir
    AT Still Univ, Kirksville, MO USA.
    Rafay, Anwar
    Contech Int Hlth Consultants, Lahore, Pakistan;Contech Sch Publ Hlth, Lahore, Pakistan.
    Rafiei, Alireza
    Mazandaran Univ Med Sci, Sch Med, Mol & Cell Biol Res Ctr, Sari, Iran.
    Rahimi, Kazem
    Univ Oxford, Oxford, England.
    Rahimi-Movaghar, Afarin
    Univ Tehran Med Sci, Iranian Natl Ctr Addict Studies, Tehran, Iran.
    Rahimi-Movaghar, Vafa
    Univ Tehran Med Sci, Sina Trauma & Surg Res Ctr, Tehran, Iran.
    Rahman, Mahfuzar
    La Trobe Univ, Austin Clin Sch Nursing, Melbourne, Vic, Australia;Univ Melbourne, Melbourne, Vic 3010, Australia;BRAC, Res & Evaluat Div, Dhaka, Bangladesh.
    Rahman, Muhammad Aziz
    Rahman, Sajjad Ur
    Sweidi Hosp, Riyadh, Saudi Arabia.
    Rai, Rajesh Kumar
    Soc Hlth & Demog Surveillance, Sufi, India.
    Raju, Bhushan
    Nizams Inst Med Sci, Hyderabad, India.
    Ram, Usha
    Int Inst Populat Sci, Mumbai, Maharashtra, India.
    Rana, Saleem M.
    Contech Int Hlth Consultants, Lahore, Pakistan;Contech Sch Publ Hlth, Lahore, Pakistan.
    Rankin, Zane
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Rasella, Davide
    Fundacao Oswaldo Cruz, Inst Goncalo Muniz, Salvador, BA, Brazil.
    Rawaf, David Laith
    Imperial Coll London, WHO Collaborating Ctr, London, England;North Hampshire Hosp, Basingstoke, Hants, England;Univ Coll London Hosp, London, England.
    Rawaf, Salman
    Imperial Coll London, London, England.
    Ray, Sarah E.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Aspacia Razo-Garcia, Christian
    Natl Inst Publ Hlth, Cuemavaca, Mexico.
    Reddy, Priscilla
    Human Sci Res Council, Cape Town, South Africa.
    Reiner, Robert C.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Reis, Cesar
    Loma Linda Univ Med Ctr, Loma Linda, CA USA.
    Reitsma, Marissa B.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Remuzzi, Giuseppe
    IRCCS, Ist Ric Farmacol Mario Negri, Milan, Italy;Azienda Sociosanitaria Terr, Bergamo, Italy;Univ Milan, Dept Biomed & Clin Sci L Sacco, Milan, Italy.
    Renzaho, Andre M. N.
    Western Sydney Univ, Ctr Hlth Res, Sydney, NSW, Australia.
    Resnikoff, Serge
    Univ New South Wales, Sch Optometry & Vision Sci, Brien Holden Vision Inst, Kensington, NSW, Australia.
    Rezaei, Satar
    Kermanshah Univ Med Sci, Sch Publ Hlth, Res Ctr Environm Determinants Hlth, Kermanshah, Iran.
    Rezai, Mohammad Sadegh
    Mazandaran Univ Med Sci, Sari, Iran.
    Ribeiro, Antonio L.
    Univ Fed Minas Gerais, Hosp Clin, Belo Horizonte, MG, Brazil.
    Rios Blancas, Maria Jesus
    Natl Inst Publ Hlth, Cuemavaca, Mexico.
    Rivera, Juan A.
    Natl Inst Publ Hlth, Cuemavaca, Mexico.
    Roever, Leonardo
    Univ Fed Uberlandia, Uberlandia, MG, Brazil.
    Ronfani, Luca
    IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy.
    Roshandel, Gholamreza
    Univ Tehran Med Sci, Digest Dis Res Inst, Tehran, Iran;Golestan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan, Iran.
    Rostami, Ali
    Babol Univ Med Sci, Sch Med, Infect Dis & Trop Med Res Ctr, Babol Sar, Iran.
    Roth, Gregory A.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Rothenbacher, Dietrich
    Ulm Univ, Inst Epidemiol & Med Biometry, Ulm, Germany.
    Roy, Ambuj
    All India Inst Med Sci, New Delhi, India.
    Roy, Nobhojit
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden;HBNI Univ, BARC Hosp, Mumbai, Maharashtra, India.
    Ruhago, George Mugambage
    Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania.
    Sabde, Yogesh Damodar
    Natl Inst Res Environm Hlth, Bhopal, India.
    Sachdev, Perminder S.
    Univ New South Wales, Sch Optometry & Vision Sci, Brien Holden Vision Inst, Kensington, NSW, Australia;Prince Wales Hosp, Randwick, NSW, Australia.
    Sadat, Nafis
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Safdarian, Mahdi
    Univ Tehran Med Sci, Sina Trauma & Surg Res Ctr, Tehran, Iran.
    Safiri, Saeid
    Maragheh Univ Med Sci, Managerial Epidemiol Res Ctr, Sch Nursing & Midwifery, Dept Publ Hlth, Maragheh, Iran.
    Sagar, Rajesh
    All India Inst Med Sci, New Delhi, India.
    Sahebkar, Amirhossein
    Univ Western Australia, Nedlands, WA, Australia;Mashhad Univ Med Sci, Mashhad, Iran.
    Sahraian, Mohammad Ali
    Univ Tehran Med Sci, MS Res Ctr, Neurosci Inst, Tehran, Iran.
    Sajadi, Haniye Sadat
    Univ Tehran Med Sci, Natl Inst Hlth Res, Tehran, Iran.
    Salama, Joseph
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Salamati, Payman
    Univ Tehran Med Sci, Sina Trauma & Surg Res Ctr, Tehran, Iran.
    Saldanha, Raphael de Freitas
    Fiocruz MS, Rio De Janeiro, Brazil.
    Salimzadeh, Hamideh
    Salomon, Joshua A.
    Harvard Univ, Harvard T H Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA.
    Samy, Abdallah M.
    Ain Shams Univ, Fac Sci, Cairo, Egypt.
    Sanabria, Juan Ramon
    Marshall Univ, Edwards Sch Med, Dept Publ Hlth, Huntington, WV USA;Case Western Reserve Univ, Cleveland, OH 44106 USA.
    Sancheti, Parag K.
    Sancheti Inst Orthopaed Rehabil, Pune, Maharashtra, India.
    Sanchez-Nino, Maria Dolores
    IIS Fdn Jimenez Diaz, Madrid, Spain.
    Santomauro, Damian
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA;Univ Queensland, Sch Publ Hlth, Brisbane, Qld, Australia;Queensland Ctr Mental Hlth Res, Brisbane, Qld, Australia.
    Santos, Itamar S.
    Univ Sao Paulo, Internal Med Dept, Sao Paulo, Brazil.
    Milicevic, Milena M. Santric
    Univ Belgrade, Ctr Sch Publ Hlth & Hlth Management, Belgrade, Serbia;Univ Belgrade, Fac Med, Inst Social Med, Belgrade, Serbia.
    Sarker, Abdur Razzaque
    Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh.
    Sarrafzadegan, Nizal
    Univ British Columbia, Fac Med, Sch Populat & Publ Hlth, Vancouver, BC, Canada;Isfahan Cardiovasc Res Inst, Esfahan, Iran.
    Sartorius, Benn
    South African Med Res Council, UKZN Gastrointestinal Canc Res Ctr, Cape Town, South Africa;Univ KwaZulu Natal, Sch Nursing & Publ Hlth, Publ Hlth Med, Durban, South Africa.
    Satpathy, Maheswar
    Utkal Univ, Ctr Adv Study Psychol, Bhubaneswar, India.
    Savic, Miloje
    Norwegian Inst Publ Hlth, Ctr Dis Burden, Oslo, Norway.
    Sawhney, Monika
    Marshall Univ, Edwards Sch Med, Dept Publ Hlth, Huntington, WV USA.
    Saxena, Sonia
    Imperial Coll London, London, England.
    Saylan, Mete I.
    Bayer Turkey, Istanbul, Turkey.
    Schaeffner, Elke
    Charite Univ Med Berlin, Berlin, Germany.
    Schmidhuber, Josef
    Food & Agr Org, Global Perspect Studies, Rome, Italy.
    Schmidt, Maria Ines
    Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil.
    Schneider, Ione J. C.
    Univ Fed Santa Catarina, Florian6poliss, Brazil.
    Schumacher, Austin E.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Schutte, Aletta E.
    South African Med Res Council, UKZN Gastrointestinal Canc Res Ctr, Cape Town, South Africa;North West Univ, Hypertens Africa Res Team, Potchefstroom, South Africa.
    Schwebel, David C.
    Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA.
    Schwendicke, Falk
    Charite Univ Med Berlin, Berlin, Germany.
    Sekerija, Mario
    Croatian Inst Publ Hlth, Croatian Natl Canc Registry, Zagreb, Croatia;Univ Zagreb, Sch Publ Hlth Dr Andrija A Tampar, Sch Med, Zagreb, Croatia.
    Sepanlou, Sadaf G.
    Univ Tehran Med Sci, Digest Dis Res Inst, Tehran, Iran.
    Servan-Mori, Edson E.
    Natl Inst Publ Hlth, Cuemavaca, Mexico.
    Shafieesabet, Azadeh
    NYU, Langone Med Ctr, Dept Rehabil Med, New York, NY 10003 USA.
    Shaikh, Masood Ali
    Shakh-Nazarova, Marina
    Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia.
    Shams-Beyranvand, Mehran
    Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Tehran, Iran.
    Sharafi, Heidar
    Deakin Univ, Middle East Liver Dis Ctr, Inst Phys Activ & Nutr, Burwood, Vic, Australia.
    Sharif-Alhoseini, Mahdi
    Univ Tehran Med Sci, Sina Trauma & Surg Res Ctr, Tehran, Iran.
    Islam, Sheikh Mohammed Shariful
    George Inst Global Hlth, New Delhi, India;Deakin Univ, Middle East Liver Dis Ctr, Inst Phys Activ & Nutr, Burwood, Vic, Australia.
    Sharma, Meenakshi
    Indian Council Med Res, Natl Inst Epidemiol, Chennai, Tamil Nadu, India.
    Sharma, Rajesh
    Delhi Technol Univ, Univ Sch Management & Entrepreneurship, Delhi, India.
    She, Jun
    Fudan Univ, Zhongshan Hosp, Dept Pulm Med, Shanghai, Peoples R China.
    Sheikh, Aziz
    Harvard Med Sch, Kigali, Rwanda.
    Shfare, Mebrahtu Teweldemedhin
    Aksum Univ, Coll Hlth Sci & Referral Hosp, Aksum, Ethiopia.
    Shi, Peilin
    Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA.
    Shields, Chloe
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Shigematsu, Mika
    Natl Inst Infect Dis, Tokyo, Japan.
    Shinohara, Yukito
    Tachikawa Hosp, Tokyo, Japan.
    Shiri, Rahman
    Univ Helsinki, Fac Med, Finnish Inst Occupat Hlth, Dept Publ Hlth,Work Org,Work Disability Program, Helsinki, Finland.
    Shirkoohi, Reza
    Univ Tehran Med Sci, Canc Res Ctr, Tehran, Iran.
    Shiue, Ivy
    Martin Luther Univ Halle Wittenberg, Inst Medizin Epidemiol Biometrie & Informat, Competence Cluster Nutr & Cardiovasc Hlth NutriCA, Saale, Germany;Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland.
    Shrime, Mark G.
    Harvard Med Sch, Kigali, Rwanda.
    Shukla, Sharvari Rahul
    Symbiosis Int Univ, Symbiosis Inst Hlth Sci, Pune, Maharashtra, India;KEM Hosp Res Ctr, Diabet Unit, Pune, Maharashtra, India.
    Siabani, Soraya
    Kermanshah Univ Med Sci, Sch Publ Hlth, Res Ctr Environm Determinants Hlth, Kermanshah, Iran;Univ Technol Sydney, Sydney, NSW, Australia.
    Sigfusdottir, Inga Dora
    Reykjavik Univ, Reykjavik, Iceland.
    Silberberg, Donald H.
    Univ Penn, Philadelphia, PA 19104 USA.
    Santos Silva, Diego Augusto
    Silva, Joao Pedro
    Univ Porto, Fac Pharm, Toxicol Grp, UCIBIO REQUIMTE, Porto, Portugal.
    Alves Silveira, Dayane Gabriele
    Brasilia Univ, Brasilia, DF, Brazil.
    Singh, Jasvinder A.
    Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA.
    Singh, Lavanya
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Singh, Narinder Pal
    Max Hosp, Ghaziabad, India.
    Singh, Virendra
    Asthma Bhawan, Jaipur, Rajasthan, India.
    Sinha, Dhirendra Narain
    Sch Prevent Oncol, Patna, Bihar, India;Natl Inst Canc Prevent, CTC Global Knowledge Hub Smokeless Tobacco, Noida, India.
    Sinke, Abiy Hiruye
    Ethiopian Med Assoc, Addis Ababa, Ethiopia.
    Sisay, Mekonnen
    Haramaya Univ, Harar, Ethiopia.
    Skirbekk, Vegard
    Columbia Univ, New York, NY 10027 USA;Norwegian Inst Publ Hlth, Ctr Dis Burden, Oslo, Norway.
    Sliwa, Karen
    Univ Cape Town, Fac Hlth Sci, Hatter Inst Cardiovasc Res Africa, Dept Psychiat, Cape Town, South Africa.
    Smith, Alison
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Soares Filho, Adauto Martins
    Sobaih, Badr H. A.
    King Khalid Univ Hosp, Riyadh, Saudi Arabia.
    Somai, Melek
    Tunisian Ctr Publ Hlth, Les Berges Du Lac, Tunisia.
    Soneji, Samir
    Dartmouth Coll, Hanover, NH 03755 USA.
    Soofi, Moslem
    Kermanshah Univ Med Sci, Sch Publ Hlth, Res Ctr Environm Determinants Hlth, Kermanshah, Iran.
    Sorensen, Reed J. D.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Soriano, Joan B.
    Inst Invest Hosp Univ Princesa IISP, Madrid, Spain;Univ Autonoma Madrid, Madrid, Spain.
    Soyiri, Ireneous N.
    Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland.
    Sposato, Luciano A.
    Western Univ, Dept Clin Neurol Sci, London, ON, Canada.
    Sreeramareddy, Chandrashekhar T.
    Int Med Univ, Dept Community Med, Kuala Lumpur, Malaysia.
    Srinivasan, Vinay
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Stanaway, Jeffrey D.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Stathopoulou, Vasiliki
    Attikon Univ Hosp, Athens, Greece.
    Steel, Nicholas
    Univ East Anglia, Norwich, Norfolk, England;Publ Hlth England, London, England.
    Stein, Dan J.
    Univ Cape Town, Fac Hlth Sci, Hatter Inst Cardiovasc Res Africa, Dept Psychiat, Cape Town, South Africa;South African Med Res Council, Unit Anxiety & Stress Disorders, Cape Town, South Africa.
    Stokes, Mark Andrew
    Deakin Univ, Middle East Liver Dis Ctr, Inst Phys Activ & Nutr, Burwood, Vic, Australia.
    Sturua, Lela
    Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia.
    Sufiyan, Muawiyyah Babale
    Ahmadu Bello Univ, Hlth Syst & Policy Res Unit, Zaria, Nigeria.
    Suliankatchi, Rizwan Abdulkader
    Minist Hlth, Riyadh, Saudi Arabia.
    Sunguya, Bruno F.
    Sur, Patrick J.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Sykes, Bryan L.
    Univ Calif Irvine, Dept Criminol Law & Soc Sociol & Publ Hlth, Irvine, CA USA.
    Sylaja, P. N.
    Sree Chitra Tirunal Inst Med Sci & Technol, Thiruvananthapuram, Kerala, India.
    Szoeke, Cassandra E. I.
    Univ Melbourne, Inst Hlth & Ageing, Melbourne, Vic 3010, Australia.
    Tabares-Seisdedos, Rafael
    Univ Valencia, INCLIVA Hlth Res Inst, Dept Med, Valencia, Spain;Univ Valencia, CIBERSAM, Dept Med, Valencia, Spain.
    Tadakamadla, Santosh Kumar
    Griffith Univ, Brisbane, Qld, Australia.
    Tadesse, Andualem Henok
    Mizan Tepi Univ, Mizan Teferi, Ethiopia.
    Taffere, Getachew Redae
    Mekelle Univ, Sch Publ Hlth, Mekelle, Ethiopia.
    Tandon, Nikhil
    All India Inst Med Sci, New Delhi, India.
    Tariku, Amare Tariku
    Univ Gondar, Gondar, Ethiopia;Univ Adelaide, Sch Med, Discipline Psychiat, Adelaide, SA, Australia.
    Taveira, Nuno
    Inst Super Ciencias Sande Egas Moniz, Almada, Portugal;Univ Lisbon, Fac Pharm, Lisbon, Portugal.
    Tehrani-Banihashemi, Arash
    Iran Univ Med Sci, Dept Community Med, Tehran, Iran;Iran Univ Med Sci, Prevent Med & Publ Hlth Res Ctr, Tehran, Iran.
    Shifa, Girma Temam
    Addis Ababa Univ, Addis Ababa, Ethiopia;Arba Minch Univ, Arba Minch, Ethiopia.
    Temsah, Mohamad-Hani
    Terkawi, Abdullah Sulieman
    Univ Virginia, Dept Anesthesiol, Charlottesville, VA USA;King Fahad Med City, Dept Anesthesiol, Riyadh, Saudi Arabia;Cleveland Clin, Consortium Cleveland Clin, Cleveland, OH 44106 USA.
    Tesema, Azeb Gebresilassie
    Mekelle Univ, Mekelle, Ethiopia.
    Tesfaye, Dawit Jember
    Hawassa Univ, Coll Med & Hlth Sci, Hawassa, Ethiopia.
    Tessema, Belay
    Univ Gondar, Gondar, Ethiopia.
    Thakur, J. S.
    Post Grad Inst Med Educ & Res, Sch Publ Hlth, Chandigarh, India.
    Thomas, Nihal
    Christian Med Coll & Hosp, Vellore, Tamil Nadu, India.
    Thompson, Matthew J.
    Univ Washington, Seattle, WA 98195 USA.
    Tillmann, Taavi
    UCL, Inst Epidemiol & Hlth, London, England.
    To, Quyen G.
    Queensland Univ Technol, Int Lab Air Qual & Hlth, Brisbane, Qld, Australia.
    Tobe-Gai, Ruoyan
    Natl Ctr Child Hlth & Dev, Tokyo, Japan.
    Tonelli, Marcello
    Univ Calgary, Calgary, AB, Canada.
    Topor-Madry, Roman
    Jagiellonian Univ, Med Coll, Fac Hlth Sci, Inst Publ Hlth, Krakow, Poland;Wroclaw Med Univ, Fac Hlth Sci, Wroclaw, Poland.
    Topouzis, Fotis
    Aristotle Univ Thessaloniki, Thessaloniki, Greece.
    Torre, Anna
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Tortajada, Miguel
    Hosp Univ Doctor Peset, Valencia, Spain;Univ Valencia, Sch Med, Valencia, Spain.
    Tran, Bach Xuan
    Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Clin Global Hlth Educ, Baltimore, MD USA;Med Univ Hanoi, Hanoi, Vietnam.
    Tran, Khanh Bao
    Tripathi, Avnish
    Univ Louisville, Sch Med, Louisville, KY 40292 USA.
    Tripathy, Srikanth Prasad
    Natl Inst Res TB, Chennai, Tamil Nadu, India.
    Troeger, Christopher
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Truelsen, Thomas
    Univ Copenhagen, Rigshosp, Dept Neurol, Copenhagen, Denmark.
    Tsoi, Derrick
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Car, Lorainne Tudor
    Nanyang Technol Univ, LKCMed, Singapore, Singapore;Imperial Coll London, London, England.
    Tuem, Kald Beshir
    Mekelle Univ, Mekelle, Ethiopia.
    Tyrovolas, Stefanos
    Univ Barcelona, CIBERSAM, Fundaci6 Sant de Joan Deu, Parc Sanitari Sant Joan de Deu, Barcelona, Spain.
    Uchendu, Uche S.
    US Dept Vet Affairs, Washington, DC USA.
    Ukwaja, Kingsley Nnanna
    Fed Teaching Hosp, Dept Internal Med, Abakaliki, Nigeria.
    Ullah, Irfan
    Gomal Univ, Gomal Ctr Biochem & Biotechnol, Dera Ismail Khan, Pakistan;Mufti Mehmood Mem Teaching Hosp, Programmat Management Drug Resistant TB Unit, TB Culture Lab, Dera Ismail Khan, Pakistan.
    Updike, Rachel
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Uthman, Olalekan A.
    Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England.
    Uzochukwu, Benjamin S. Chudi
    Univ Nigeria, Enugu Campus, Enugu, Nigeria.
    Ruben Valdez, Pascual
    Sociedad Argentina Med, Buenos Aires, DF, Argentina;Hosp Velez Sarsfield, Buenos Aires, DF, Argentina.
    van Boven, Job F. M.
    Univ Groningen, Groningen, Netherlands.
    Varughese, Santosh
    Christian Med Coll & Hosp, Vellore, Tamil Nadu, India.
    Vasankari, Tommi
    UKK Inst Hlth Promot Res, Tampere, Finland.
    Venketasubramanian, Narayanaswamy
    Raffles Hosp, Raffles Neurosci Ctr, Singapore, Singapore.
    Violante, Francesco S.
    Univ Bologna, Bologna, Italy.
    Vladimirov, Sergey K.
    Fed Res Inst Hlth Org & Informat, Moscow, Russia.
    Vlassov, Vasiliy Victorovich
    Natl Res Univ Higher Sch Econ, Moscow, Russia.
    Vollset, Stein Emil
    Norwegian Inst Publ Hlth, Ctr Dis Burden, Oslo, Norway.
    Vos, Theo
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Wagnew, Fasil
    Debre Markos Univ, Debre Markos, Ethiopia.
    Waheed, Yasir
    Fdn Univ, Islamabad, Pakistan.
    Wallin, Mitchell T.
    VA Med Ctr, Washington, DC USA;Georgetown Univ, Neurol Dept, Washington, DC USA.
    Walson, Judd L.
    Univ Washington, Seattle, WA 98195 USA;Nat Hist Museum, London, England.
    Wang, Yafeng
    Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China;Xi An Jiao Tong Univ, Affiliated Hosp 1, Xian, Shaanxi, Peoples R China;Univ Sao Paulo, Med Sch, Sao Paulo, SP, Brazil.
    Wang, Yuan-Pang
    Wassie, Molla Mesele
    Univ Gondar, Gondar, Ethiopia;Univ Adelaide, Adelaide, SA, Australia.
    Weaver, Marcia R.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Weiderpass, Elisabete
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Stockholm, Sweden;Canc Registry Norway, Inst Populat Based Canc Res, Dept Res, Oslo, Norway;Arctic Univ Norway, Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway;Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland.
    Weintraub, Robert G.
    Univ Melbourne, Melbourne, Vic 3010, Australia;Royal Childrens Hosp, Melbourne, Vic, Australia;Murdoch Childrens Res Inst, Melbourne, Vic, Australia.
    Weiss, Jordan
    Univ Penn, Philadelphia, PA 19104 USA.
    Weldegwergs, Kidu Gidey
    Mekelle Univ, Mekelle, Ethiopia.
    Werdecker, Andrea
    Fed Inst Populat Res, Competence Ctr Mortal Follow Up German Natl Cohor, Wiesbaden, Germany.
    West, T. Eoin
    Univ Washington, Seattle, WA 98195 USA.
    Westerman, Ronny
    Fed Inst Populat Res, Competence Ctr Mortal Follow Up German Natl Cohor, Wiesbaden, Germany;German Natl Cohort Consortium, Heidelberg, Germany.
    White, Richard G.
    London Sch Hyg & Trop Med, London, England.
    Whiteford, Harvey A.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA;Univ Queensland, Sch Publ Hlth, Brisbane, Qld, Australia;Queensland Ctr Mental Hlth Res, Brisbane, Qld, Australia.
    Widecka, Justyna
    VitroLive Sp Zoo, Szczecin, Poland.
    Winkler, Andrea Sylvia
    Tech Univ Munich, Klinikum Rechts Isar, Ctr Global Hlth, Dept Neurol, Munich, Germany;Univ Oslo, Ctr Global Hlth, Inst Hlth & Soc, Oslo, Norway.
    Wiysonge, Charles Shey
    Stellenbosch Univ, Cape Town, South Africa;South African Med Res Council, Cape Town, South Africa.
    Wolfe, Charles D. A.
    Kings Coll London, Div Hlth & Social Care Res, London, England;Kings Coll London, London, England;Guys & St Thomas NHS Fdn Trust, Natl Inst Hlth, Res Comprehens Biomed Res Ctr, London, England.
    Wondimkun, Yohanes Ayele
    Haramaya Univ, Harar, Ethiopia.
    Workicho, Abdulhalik
    Jimma Univ, Jimma, Ethiopia;Univ Ghent, Ghent, Belgium.
    Wyper, Grant M. A.
    NHS Natl Serv Scotland, Glasgow, Lanark, Scotland;Univ Strathclyde, Glasgow, Lanark, Scotland.
    Xavier, Denis
    St Johns Med Coll & Res Inst, Bangalore, Karnataka, India.
    Xu, Gelin
    Nanjing Univ, Jinling Hosp, Sch Med, Dept Neurol, Nanjing, Jiangsu, Peoples R China.
    Yan, Lijing L.
    Duke Kunshan Univ, Global Hlth Res Ctr, Kunshan, Peoples R China.
    Yano, Yuichiro
    Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA.
    Yaseri, Mehdi
    Shahid Beheshti Univ Med Sci, Ophthalm Res Ctr, Tehran, Iran.
    Yimer, Nigus Bililign
    Woldia Univ, Woldia, Ethiopia.
    Yin, Peng
    Chinese Ctr Dis Control & Prevent, Natl Ctr Chron & Noncommunicable Dis Control & Pr, Beijing, Peoples R China.
    Yip, Paul
    Univ Hong Kong, Hong Kong Jockey Club Ctr Suicide Res & Prevent, Social Work & Social Adm Dept, Hong Kong, Hong Kong, Peoples R China.
    Yirsaw, Biruck Desalegn
    Addis Ababa Univ, Addis Ababa, Ethiopia;Univ South Australia, Mawson Lakes, SA, Australia.
    Yonemoto, Naohiro
    Kyoto Univ, Sch Publ Hlth, Dept Biostat, Kyoto, Japan.
    Yonga, Gerald
    Aga Khan Univ, NCD Res Policy Unit, Nairobi, Kenya.
    Yoon, Seok-Jun
    Korea Univ, Coll Med, Dept Prevent Med, S, Seoul, South Korea.
    Yotebieng, Marcel
    Ohio State Univ, Columbus, OH 43210 USA;Univ Kinshasa, Sch Publ Hlth, Kinshasa, DEM REP CONGO.
    Younis, Mustafa Z.
    Jackson State Univ, Jackson, MS 39217 USA.
    Yu, Chuanhua
    Wuhan Univ, Sch Publ Hlth, Global Hlth Inst, Dept Epidemiol & Biostat, Wuhan, Hubei, Peoples R China.
    Zadnik, Vesna
    Inst Oncol Ljubljana, Epidemiol & Canc Registry, Ljubljana, Slovenia.
    Zaidi, Zoubida
    Univ Hosp Setif, Setif, Algeria.
    Zaki, Maysaa El Sayed
    Mansoura Univ, Fac Med, Mansoura, Egypt.
    Bin Zaman, Sojib
    Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh.
    Zamani, Mohammad
    Babol Univ Med Sci, Babol Sar, Iran.
    Zenebe, Zerihun Menlkalew
    Mekelle Univ, Mekelle, Ethiopia.
    Zhou, Maigeng
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA;Chinese Ctr Dis Control & Prevent, Natl Ctr Chron & Noncommunicable Dis Control & Pr, Beijing, Peoples R China.
    Zhu, Jun
    Natl Off MCH Surveillance China, Chengdu, Peoples R China.
    Zimsen, Stephanie R. M.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Zipkin, Ben
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Zodpey, Sanjay
    Publ Hlth Fdn India, Gurugram, India.
    Zuhlke, Liesl Joanna
    Red Cross War Mem Childrens Hosp, Cape Town, South Africa.
    Murray, Christopher J. L.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Lozano, Rafael
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.
    Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: a systematic analysis from the Global Burden of Disease Study 20162018In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 391, no 10136, p. 2236-2271Article in journal (Refereed)
    Abstract [en]

    Background: A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016.

    Methods: Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita.

    Findings: In 2016, HAQ Index performance spanned from a high of 97.1 (95% UI 95.8-98.1) in Iceland, followed by 96.6 (94.9-97.9) in Norway and 96.1 (94.5-97.3) in the Netherlands, to values as low as 18.6 (13.1-24.4) in the Central African Republic, 19.0 (14.3-23.7) in Somalia, and 23.4 (20.2-26.8) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91.5 (89.1-936) in Beijing to 48.0 (43.4-53.2) in Tibet (a 43.5-point difference), while India saw a 30.8-point disparity, from 64.8 (59.6-68.8) in Goa to 34.0 (30.3-38.1) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4.8-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20.9-point to 17.0-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17.2-point to 20.4-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries.

    Interpretation: GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle-SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view and subsequent provision of quality health care for all populations.

  • 39. Gakidou, E
    et al.
    Afshin, A
    Abajobir, AA
    Abate, KH
    Abbafati, C
    Abbas, KM
    Abd-Allah, A
    Abdulle, AM
    Abera, F
    Aboyans, v
    Abu-Raddad, LJ
    Abu-Rmeileh, NME
    Abyu, GY
    Ärnlöv, Johan
    Karolinska university; Dalarna University.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Artaman, A
    Aryal, KK
    Asayesh, H
    Zhang, X
    Zimsen, SRM
    Zipkin, B,
    Zodpey, S
    Lim, SS
    Murray, CJL
    Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2016: a systematic analysis for the Global Burden of Disease Study 20162017In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 390, no 10100, p. 1345-1422Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of risk factor exposure and attributable burden of disease. By providing estimates over a long time series, this study can monitor risk exposure trends critical to health surveillance and inform policy debates on the importance of addressing risks in context.

    METHODS: We used the comparative risk assessment framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2016. This study included 481 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk (RR) and exposure estimates from 22 717 randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources, according to the GBD 2016 source counting methods. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. Finally, we explored four drivers of trends in attributable burden: population growth, population ageing, trends in risk exposure, and all other factors combined.

    FINDINGS: Since 1990, exposure increased significantly for 30 risks, did not change significantly for four risks, and decreased significantly for 31 risks. Among risks that are leading causes of burden of disease, child growth failure and household air pollution showed the most significant declines, while metabolic risks, such as body-mass index and high fasting plasma glucose, showed significant increases. In 2016, at Level 3 of the hierarchy, the three leading risk factors in terms of attributable DALYs at the global level for men were smoking (124·1 million DALYs [95% UI 111·2 million to 137·0 million]), high systolic blood pressure (122·2 million DALYs [110·3 million to 133·3 million], and low birthweight and short gestation (83·0 million DALYs [78·3 million to 87·7 million]), and for women, were high systolic blood pressure (89·9 million DALYs [80·9 million to 98·2 million]), high body-mass index (64·8 million DALYs [44·4 million to 87·6 million]), and high fasting plasma glucose (63·8 million DALYs [53·2 million to 76·3 million]). In 2016 in 113 countries, the leading risk factor in terms of attributable DALYs was a metabolic risk factor. Smoking remained among the leading five risk factors for DALYs for 109 countries, while low birthweight and short gestation was the leading risk factor for DALYs in 38 countries, particularly in sub-Saharan Africa and South Asia. In terms of important drivers of change in trends of burden attributable to risk factors, between 2006 and 2016 exposure to risks explains an 9·3% (6·9-11·6) decline in deaths and a 10·8% (8·3-13·1) decrease in DALYs at the global level, while population ageing accounts for 14·9% (12·7-17·5) of deaths and 6·2% (3·9-8·7) of DALYs, and population growth for 12·4% (10·1-14·9) of deaths and 12·4% (10·1-14·9) of DALYs. The largest contribution of trends in risk exposure to disease burden is seen between ages 1 year and 4 years, where a decline of 27·3% (24·9-29·7) of the change in DALYs between 2006 and 2016 can be attributed to declines in exposure to risks.

    INTERPRETATION: Increasingly detailed understanding of the trends in risk exposure and the RRs for each risk-outcome pair provide insights into both the magnitude of health loss attributable to risks and how modification of risk exposure has contributed to health trends. Metabolic risks warrant particular policy attention, due to their large contribution to global disease burden, increasing trends, and variable patterns across countries at the same level of development. GBD 2016 findings show that, while it has huge potential to improve health, risk modification has played a relatively small part in the past decade.

  • 40.
    Govorov, Igor
    et al.
    Karolinska Institutet, Department of Women's and Children's Health, Stockholm, Sweden.
    Bremme, Katarina
    Karolinska Institutet, Department of Women's and Children's Health, Stockholm, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Holmström, Margareta
    Karolinska University Hospital Solna, Department of Medicine, Stockholm, Sweden.
    Komlichenko, Eduard
    Almazov National Medical Research Centre, Institution of Pediatrics and Perinatology, Saint-Petersburg, Russia.
    Chaireti, Roza
    Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden.
    Mints, Miriam
    Karolinska Institutet, Department of Women's and Children's Health, Stockholm, Sweden.
    Blood inflammatory and endothelial markers in women with von Willebrand disease2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 1, article id e0210544Article in journal (Refereed)
    Abstract [en]

    Introduction: VWD-affected females often experience menorrhagia. Periodical fluctuations of the sex steroids during the menstrual cycle cause changes both in the coagulation and immune system. The aim of the current study was to assess the changes in selected inflammatory and endothelial markers in women with VWD during two phases of the menstrual cycle (follicular and luteal) and to compare it with corresponding data from healthy controls.

    Materials and methods: The study group included 12 VWD-affected females with regular menstrual cycle, with none of them being prescribed hormone treatment. They were not pregnant or breastfeeding. The control group consisted of 102 healthy females, matched for age and BMI.

    Results: Within the VWD group, endostatin was higher during the follicular phase, compared to the luteal phase, although the difference was not significant (p = 0.062). sICAM-1 and IL-6 were higher in VWD-affected females, compared to the controls, sVCAM-1, cathepsin S and sP-selectin were lower (p<0.003 for all cases). The pattern was constant throughout the menstrual cycle.

    Conclusions: Higher levels of endostatin during early follicular phase could potentially predispose women with VWD to the development of heavy menstrual bleeding, due to antiangiogenic properties and ability to suppress several coagulation factors. Lower p-selectin levels in VWD group, compared to controls, may also contribute to the bleeding tendency. Changes in other proteins, involved in angiogenesis are hypothetically related to the formation of angiodysplasia—common complication of VWF deficiency. The latter statement requires confirmation in larger studies.

  • 41. Griswold, MG
    et al.
    Fullman, N
    Hawley, C
    Arian, N
    Zimsen, SRM,
    Tymeson, HD
    Venkateswaran, V
    Tapp, AD
    Forouzanfar, MH
    Salama, JS
    Ärnlöv, Johan
    Karolinska Inst, Dept Neurobiol, Stockholm, Sweden; Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Carrero, JJ
    Carvalho, F
    Yotebieng, M
    Younis, MZ
    Zachariah, G
    Zaidi, Z
    Zamani, M
    Zhang, X
    Zodpey, S
    Mokdad, AH
    Naghavi, M
    Murray, CJL
    Gakidou, E
    Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 20162018In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 392, no 10152, p. 1015-1035Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older.

    METHODS: Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health.

    FINDINGS: Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2·2% (95% uncertainty interval [UI] 1·5-3·0) of age-standardised female deaths and 6·8% (5·8-8·0) of age-standardised male deaths. Among the population aged 15-49 years, alcohol use was the leading risk factor globally in 2016, with 3·8% (95% UI 3·2-4·3) of female deaths and 12·2% (10·8-13·6) of male deaths attributable to alcohol use. For the population aged 15-49 years, female attributable DALYs were 2·3% (95% UI 2·0-2·6) and male attributable DALYs were 8·9% (7·8-9·9). The three leading causes of attributable deaths in this age group were tuberculosis (1·4% [95% UI 1·0-1·7] of total deaths), road injuries (1·2% [0·7-1·9]), and self-harm (1·1% [0·6-1·5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27·1% (95% UI 21·2-33·3) of total alcohol-attributable female deaths and 18·9% (15·3-22·6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0·0-0·8) standard drinks per week.

    INTERPRETATION: Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption.

    FUNDING: Bill & Melinda Gates Foundation.

  • 42. Gyllenhammar, Irina
    et al.
    Diderholm, Barbro
    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), Pediatric Endocrinology.
    Gustafsson, Jan
    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), Pediatric Endocrinology.
    Berger, Urs
    Ridefelt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Benskin, Jonathan P
    Lignell, Sanna
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Glynn, Anders
    Perfluoroalkyl acid levels in first-time mothers in relation to offspring weight gain and growth2018In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 111, p. 191-199Article in journal (Refereed)
    Abstract [en]

    We investigated if maternal body burdens of perfluoroalkyl acids (PFAAs) at the time of delivery are associated with birth outcome and if early life exposure (in utero/nursing) is associated with early childhood growth and weight gain. Maternal PFAA body burdens were estimated by analysis of serum samples from mothers living in Uppsala County, Sweden (POPUP), sampled three weeks after delivery between 1996 and 2011. Data on child length and weight were collected from medical records and converted into standard deviation scores (SDS). Multiple linear regression models with appropriate covariates were used to analyze associations between maternal PFAA levels and birth outcomes (n=381). After birth Generalized Least Squares models were used to analyze associations between maternal PFAA and child growth (n=200). Inverse associations were found between maternal levels of perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), and birth weight SDS with a change of -0.10 to -0.18 weight SDS for an inter-quartile range (IQR) increase in ng/g PFAA. After birth, weight and length SDS were not significantly associated with maternal PFAA. However, BMI SDS was significantly associated with PFOA, PFNA, and PFHxS at 3 and 4years of age, and with PFOS at 4 and 5years of age. If causal, these associations suggest that PFAA affects fetal and childhood body development in different directions.

  • 43.
    Halvorsen, Cecilia Pegelow
    et al.
    Karolinska Inst, Dept Clin Res & Educ, Sodersjukhuset, Stockholm, Sweden;Sachs Children & Youth Hosp, Neonatal Unit, Stockholm, Sweden.
    Olson, Linus
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden;TRAC Sweden Vietnam, Hanoi, Vietnam.
    Araujo, Ana Catarina
    Calmark Sweden AB, Stockholm, Sweden.
    Karlsson, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Calmark Sweden AB, Stockholm, Sweden.
    Nguyen, Trang Thi
    Khu, Dung T. K.
    TRAC Sweden Vietnam, Hanoi, Vietnam;Vietnam Natl Childrens Hosp, Neonatal Intens Care Unit, Hanoi, Vietnam.
    Le, Ha T. T.
    Vietnam Natl Childrens Hosp, Neonatal Intens Care Unit, Hanoi, Vietnam;Res Inst Child Hlth, Hanoi, Vietnam.
    Nguyen, Hoa T. B.
    Vietnam Natl Childrens Hosp, Neonatal Intens Care Unit, Hanoi, Vietnam;Res Inst Child Hlth, Hanoi, Vietnam.
    Winbladh, Birger
    Karolinska Inst, Dept Clin Res & Educ, Sodersjukhuset, Stockholm, Sweden.
    Russom, Aman
    KTH Royal Inst Technol, Div Nanobiotechnol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth,Sci Life Lab, Stockholm, Sweden.
    A rapid smartphone-based lactate dehydrogenase test for neonatal diagnostics at the point of care2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 9301Article in journal (Refereed)
    Abstract [en]

    There is a growing recognition of the importance of point-of-care tests (POCTs) for detecting critical neonatal illnesses to reduce the mortality rate in newborns, especially in low-income countries, which account for 98 percent of reported neonatal deaths. Lactate dehydrogenase (LDH) is a marker of cellular damage as a result of hypoxia-ischemia in affected organs. Here, we describe and test a POC LDH test direct from whole blood to provide early indication of serious illness in the neonate. The sample-inresult- out POC platform is specifically designed to meet the needs at resource-limited settings. Plasma is separated from whole blood on filter paper with dried-down reagents for colorimetric reaction, combined with software for analysis using a smartphone. The method was clinically tested in newborns in two different settings. In a clinical cohort of newborns of Stockholm (n = 62) and Hanoi (n = 26), the value of R using Pearson's correlation test was 0.91 (p < 0.01) and the R-2 = 0.83 between the two methods. The mean LDH (+/- SD) for the reference method vs. the POC-LDH was 551 (+/- 280) U/L and 552 (+/- 249) U/L respectively, indicating the clinical value of LDH values measured in minutes with the POC was comparable with standardized laboratory analyses.

  • 44. Hardt, Uta
    et al.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Gunnarsson, Iva
    Clancy, Robert M
    Petri, Michelle
    Buyon, Jill P
    Silverman, Gregg J
    Svenungsson, Elisabet
    Grönwall, Caroline
    Autoimmune reactivity to malondialdehyde adducts in systemic lupus erythematosus is associated with disease activity and nephritis2018In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 20, article id 36Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Immunoglobulin M (IgM) autoreactivity to malondialdehyde (MDA) protein modifications is part of the natural antibody repertoire in health and may have beneficial functions. In contrast, IgG anti-MDA are increased in chronic inflammation and autoimmunity and may instead have pathogenic properties.

    METHODS: Herein, we investigated serum IgG anti-MDA levels by enzyme-linked immunosorbent assay (ELISA) in 398 systemic lupus erythematosus (SLE) patients in the Swedish Karolinska SLE cohort and compared these to findings in 225 US SLE patients from New York University and Johns Hopkins University.

    RESULTS: In two independent cohorts, IgG anti-MDA levels correlated positively with disease activity by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; p < 0.0001, Spearman R = 0.3). Meta-analysis found an odds ratio of 2.7 (confidence interval (CI) 1.9-3.9; p < 0.0001) for high anti-MDA IgG levels with active disease (SLEDAI ≥ 6). Furthermore, IgG anti-MDA correlated directly with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), soluble tumor necrosis factor receptors (sTNFR-1, sTNFR-2), and vascular cell adhesion molecule 1 (VCAM-1) measurements, and inversely with complement factors (C1q, C2, C3, C4). Importantly, IgG anti-MDA levels were significantly elevated in SLE patients with active nephritis (p = 0.0005) and correlated with cystatin C estimated glomerular filtration rate and albuminuria.

    CONCLUSIONS: Elevated IgG anti-MDA in SLE patients was associated with high disease activity, with active lupus nephritis, and with biomarkers of systemic inflammation. This natural antibody reactivity may have potential prognostic utility, and may also actively contribute to pathogenesis.

  • 45.
    Hardt, Uta
    et al.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Gunnarsson, Iva
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Clancy, Robert M.
    NYU, Sch Med, Dept Med, Div Rheumatol, New York, NY USA..
    Silverman, Gregg J.
    NYU, Sch Med, Dept Med, Div Rheumatol, New York, NY USA..
    Svenungsson, Elisabet
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Gronwall, Caroline
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Autoimmune reactivity to malondialdehyde adducts in SLE is associated with high disease activity2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 330-330Article in journal (Other academic)
  • 46. Hay, SI
    et al.
    Abajobir, AA
    Abate, KH
    Abbafati, C
    Abbas, KM
    Abd-Allah, F
    Abdulkader, RS
    Abdulle, AM
    Abebo, TA
    Abera, SF
    Aboyans, V
    Abu-Raddad, LJ
    Ärnlöv, Johan
    Karolinska institute, Dept Neurobiol, Div Family Med & Primary Care, Care Sci & Soc, Stockholm, Sweden; Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden .
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Zaki, MES
    Zegeye, EA
    Zenebe, ZM
    Zhang, X
    Zheng, Y
    Zhou, M
    Zipkin, B
    Zodpey, S
    Zoeckler, L
    Zuhlke, LJ
    Murray, CJL
    Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.2017In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 390, no 10100, p. 1260-1344, article id S0140-6736(17)32130-XArticle in journal (Refereed)
    Abstract [en]

    BACKGROUND: Measurement of changes in health across locations is useful to compare and contrast changing epidemiological patterns against health system performance and identify specific needs for resource allocation in research, policy development, and programme decision making. Using the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we drew from two widely used summary measures to monitor such changes in population health: disability-adjusted life-years (DALYs) and healthy life expectancy (HALE). We used these measures to track trends and benchmark progress compared with expected trends on the basis of the Socio-demographic Index (SDI).

    METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2016. We calculated DALYs by summing years of life lost and years of life lived with disability for each location, age group, sex, and year. We estimated HALE using age-specific death rates and years of life lived with disability per capita. We explored how DALYs and HALE differed from expected trends when compared with the SDI: the geometric mean of income per person, educational attainment in the population older than age 15 years, and total fertility rate.

    FINDINGS: The highest globally observed HALE at birth for both women and men was in Singapore, at 75·2 years (95% uncertainty interval 71·9-78·6) for females and 72·0 years (68·8-75·1) for males. The lowest for females was in the Central African Republic (45·6 years [42·0-49·5]) and for males was in Lesotho (41·5 years [39·0-44·0]). From 1990 to 2016, global HALE increased by an average of 6·24 years (5·97-6·48) for both sexes combined. Global HALE increased by 6·04 years (5·74-6·27) for males and 6·49 years (6·08-6·77) for females, whereas HALE at age 65 years increased by 1·78 years (1·61-1·93) for males and 1·96 years (1·69-2·13) for females. Total global DALYs remained largely unchanged from 1990 to 2016 (-2·3% [-5·9 to 0·9]), with decreases in communicable, maternal, neonatal, and nutritional (CMNN) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). The exemplars, calculated as the five lowest ratios of observed to expected age-standardised DALY rates in 2016, were Nicaragua, Costa Rica, the Maldives, Peru, and Israel. The leading three causes of DALYs globally were ischaemic heart disease, cerebrovascular disease, and lower respiratory infections, comprising 16·1% of all DALYs. Total DALYs and age-standardised DALY rates due to most CMNN causes decreased from 1990 to 2016. Conversely, the total DALY burden rose for most NCDs; however, age-standardised DALY rates due to NCDs declined globally.

    INTERPRETATION: At a global level, DALYs and HALE continue to show improvements. At the same time, we observe that many populations are facing growing functional health loss. Rising SDI was associated with increases in cumulative years of life lived with disability and decreases in CMNN DALYs offset by increased NCD DALYs. Relative compression of morbidity highlights the importance of continued health interventions, which has changed in most locations in pace with the gross domestic product per person, education, and family planning. The analysis of DALYs and HALE and their relationship to SDI represents a robust framework with which to benchmark location-specific health performance. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform health policies, health system improvement initiatives, targeted prevention efforts, and development assistance for health, including financial and research investments for all countries, regardless of their level of sociodemographic development. The presence of countries that substantially outperform others suggests the need for increased scrutiny for proven examples of best practices, which can help to extend gains, whereas the presence of underperforming countries suggests the need for devotion of extra attention to health systems that need more robust support.

    FUNDING: Bill & Melinda Gates Foundation.

  • 47.
    Held, Claes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    White, Harvey D.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand..
    Stewart, Ralph A. H.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand..
    Budaj, Andrzej
    Grochowski Hosp, Postgrad Med Sch, Warsaw, Poland..
    Cannon, Christopher P.
    Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA..
    Hochman, Judith S.
    NYU, Dept Med, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA..
    Koenig, Wolfgang
    Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, Ulm, Germany.;Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany..
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Steg, Philippe Gabriel
    Hop Bichat Claude Bernard, AP HP, Dept Hosp Univ FIRE, Paris, France.;Paris Diderot Univ, Sorbonne Paris Cite, Paris, France.;NHLI Imperial Coll, Royal Brompton Hosp, ICMS, London, England.;INSERM, FACT, U1148, Paris, France..
    Soffer, Joseph
    GlaxoSmithKline, Metab Pathways & Cardiovasc Therapeut Area, Collegeville, PA USA..
    Weaver, Douglas
    Henry Ford Heart & Vasc Inst, Detroit, MI USA..
    Östlund, Ollie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, 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.
    Inflammatory Biomarkers Interleukin-6 and C-Reactive Protein and Outcomes in Stable Coronary Heart Disease: Experiences From the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial2017In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 6, no 10, article id e005077Article in journal (Refereed)
    Abstract [en]

    Background

    Evaluation of cardiovascular prognosis in patients with stable coronary heart disease is based on clinical characteristics and biomarkers indicating dysglycemia, dyslipidemia, renal dysfunction, and possibly cardiac dysfunction. Inflammation plays a key role in atherosclerosis, but the association between inflammatory biomarkers and clinical outcomes is less studied in this population.

    Methods and Results

    Overall, 15 828 patients with coronary heart disease in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial werer and randomized to treatment with darapladib or placebo and observed for a median of 3.7 years. In 14 611 patients, levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein were measured in plasma samples: median levels were2.1 (interquartile range, 1.4-3.2) ng/Land1.3 (interquartile range, 0.6-3.1) mg/L, respectively. Associations between continuous levels or quartile groups and adjudicated outcomes were evaluated by spline graphs and Cox regression adjusted for clinical factors and cardiovascular biomarkers. IL-6 was associated with increased risk of major adverse cardiovascular events (quartile 4 versus quartile 1 hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.30-1.97; P< 0.0001); cardiovascular death (HR, 2.15; 95% CI, 1.53-3.04; P< 0.0001); myocardial infarction (HR, 1.53; 95% CI, 1.14-2.04; P< 0.05); all-cause mortality (HR, 2.11; 95% CI, 1.62-2.76; P< 0.0001); and risk of hospitalization for heart failure (HR, 2.28; 95% CI, 1.34-3.89; P< 0.001). Cancer death was doubled in the highest IL-6 quartile group (HR, 2.34; 95% CI, 1.20-4.53; P< 0.05). High-sensitivity C-reactive protein was associated with both cardiovascular and non-cardiovascular events in the unadjusted model, but these did not remain after multivariable adjustments.

    Conclusions

    IL-6, an upstream inflammatory marker, was independently associated with the risk of major adverse cardiovascular events, cardiovascular and all-cause mortality, myocardial infarction, heart failure, and cancer mortality in patients with stable coronary heart disease. IL-6 might reflect a pathophysiological process involved in the development of these events.

  • 48.
    Hellman, U
    et al.
    Department of Public Health and Clinical Medicine , Umeå University , Umeå , Sweden..
    Engström-Laurent, A
    Department of Public Health and Clinical Medicine , Umeå University , Umeå , Sweden..
    Larsson, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lindqvist, U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hyaluronan concentration and molecular mass in psoriatic arthritis: biomarkers of disease severity, resistance to treatment, and outcome.2019In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, p. 1-10Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Low molecular mass hyaluronan causes inflammatory processes and can act as a pro-inflammatory cytokine in skin and other sites of activity in psoriatic arthritis (PsA). This study investigated whether the molecular mass distribution of hyaluronan (HA) in skin and the quantity of circulating HA are related to the clinical inflammatory picture in PsA with active disease and to the effect of treatment with anti-tumour necrosis factor-α (anti-TNF-α) adalimumab.

    METHODS: Twenty patients with TNF-α-naïve active polyarticular PsA were included in this prospective clinical trial of treatment with 40 mg s.c. adalimumab according to standard procedure. Clinical activity, patients' assessments, and skin biopsies were captured at inclusion and at the 12 week follow-up. Ten healthy individuals were recruited for comparison of HA analyses. Histochemistry of skin inflammation, serum HA, and molecular mass of HA were determined.

    RESULTS: Overall improvements in clinical parameters were observed. Eight of 18 patients reached minimum disease activity after 12 weeks and disease activity was significantly reduced (p < 0.0001). Patients with elevated serum HA values were significantly older, had later onset of arthritis and more deformed joints, still had swollen joints after treatment, and had more circulating inflammatory biomarkers. More severe disease pathology showed a wide spectrum of high-molecular-mass HA accompanied by low mass HA. The treatment appears partly to normalize the HA mass distribution.

    CONCLUSION: HA concentration and mass seem to be two possible factors in the inflammatory pathology of PsA acting as biomarkers for disease severity, resistance to treatment, and worse outcome.

  • 49.
    Helmersson, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ridefelt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Boija, Elisabet Eriksson
    External Qual Assessment Clin Lab Investigat Equa, Uppsala, Sweden.
    Nordin, Gunnar
    External Qual Assessment Clin Lab Investigat Equa, Uppsala, Sweden.
    Lower creatinine concentration values and lower inter-laboratory variation among Swedish hospital laboratories in 2014 compared to 1996: results from the Equalis external quality assessment program2019In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 57, no 6, p. 838-844Article in journal (Refereed)
    Abstract [en]

    Background:

    Creatinine measurement for estimation of glomerular filtration rate (GFR) is a frequently used laboratory test. Differences in analytic creatinine methods have caused large inter-laboratory variation. International and national standardization efforts have been made in the last decade.

    Methods:

    This study describes the results of the standardization efforts in Sweden by summarizing data for creatinine concentration in blood plasma in the Equalis quality assessment program during 1996-2014.

    Results:

    Non-compensated Jaffe methods dominated in 1996-2001 (91 of 103 laboratories; 90%) and were then gradually replaced by either compensated Jaffe methods or enzymatic creatinine methods. In 2014 a majority of Swedish hospital laboratories (139 of 159; 87%) used enzymatic methods. The reported mean creatinine value by the Swedish laboratories was about 10 mu mol/L higher than the isotope dilution mass spectrometry (IDMS) assured reference value in 2003, but consistent with the reference value from 2009 to 2014. The inter-laboratory CV was 7%-9% for creatinine values until 2007, and thereafter gradually decreased to about 4%-5% in 2014.

    Conclusions:

    The introduction of enzymatic methods in Swedish laboratories has contributed to achieving a low inter-laboratory variation. Also, the reported values are lower for enzymatic methods compared to Jaffe methods, and the values obtained with enzymatic methods were consistent with IDMS certified values established at reference laboratories. Thus, many Swedish hospital laboratories reported 10 mu mol/L lower, and more true, creatinine concentrations in 2012 than in 2003, which may cause bias in longitudinal studies.

  • 50.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hammarström, Kristina Höög
    Karolinska Univ Hosp, Ctr Inherited Metab Dis, Stockholm, Sweden.
    Palmberg, Kicki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Backman-Johansson, Carolina
    Karolinska Univ Hosp, Ctr Inherited Metab Dis, Stockholm, Sweden.
    Evaluation of Nova StatStrip and FreeStyle Precision Pro blood ketone tests using 3-hydroxybutyrate doped samples2019In: Journal of clinical laboratory analysis (Print), ISSN 0887-8013, E-ISSN 1098-2825, Vol. 33, no 4, article id e22851Article in journal (Other academic)
    Abstract [en]

    Background The most clinically useful blood ketone in the diagnosis, management, and recovery of diabetes ketoacidosis in both adults and children is 3-hydroxybutyrate. In the absence of laboratory routine methods, several point-of-care methods are in use, but very few clinical evaluations are published. Methods This study evaluates linearity and reproducibility of two handheld point-of-care meters for blood 3-hydroxybutyrate measurement for hospital use, Nova StatStrip, and FreeStyle Precision Pro. Whole blood from healthy volunteers was spiked with different concentrations of a 3-hydroxybutyrate solution and tested on the point-of-care instruments. The results were compared with plasma 3-hydroxybutyrate that was analyzed with a laboratory enzymatic end point spectrophotometric reference method. Results Blood 3-hydroxybutyrate on StatStrip was linear with the reference method up to approximately 4 mmol/L, and FreeStyle was linear up to 6 mmol/L. At higher concentrations, the point-of-care instruments gave falsely too low results, especially the StatStrip meter. The FreeStyle meter had better precision and less bias than StatStrip. Conclusion In the acute setting of diabetes ketoacidosis, blood 3-hydroxybutyrate in the higher ranges should be interpreted with caution as the point-of-care meters are less accurate there.

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