The Author's Reply [4]

[No abstract available]651181Happé, F.G.E., Brownell, H., Winner, E., Acquired 'theory of mind' impairments following stroke (1999) Cognition, 70, pp. 211-240Stone, V.E., Baron-Cohen, S., Knight, R.T., Frontal lobe contribution to theory of mind (1998) J Cognitive Neurosci, 10, pp. 640-656Stuss, D.T., Gallup, G.G., Alexander, M.P., (2001) The frontal lobes are necessary for 'theory of mind, 124, pp. 279-286. , BrainBird, C.M., Castelli, F., Malik, O., Frith, U., Husain, M., The impact of extensive medial frontal lobe damage on "theory of mind" and cognition (2004) Brain, 127, pp. 914-92

Accuracy Of Prospective Memory Tests In Mild Alzheimer's Disease [acurácia Dos Testes De Memória Prospectiva Na Doença De Alzheimer Leve]

Objectives: To verify the accuracy of prospective memory (ProM) tests in Alzheimer's disease (AD). Methods: Twenty mild AD patients (CDR 1), and 20 controls underwent Digit Span (DS), Trail Making (TM) A and B, visual perception, Rey Auditory-Verbal Learning tests, and Cornell Scale for Depression. AD diagnosis was based on DSM-IV and NINCDS-ADRDA criteria. ProM was assessed with the appointment and belonging subtests of Rivermead Behavioral Memory Test (RBMT); and with two new tests (the clock and animal tests). Results: AD patients had a worse performance than controls on the majority of tests, except DS forward and TM-A. There was no correlation between RBMT and the new ProM tests. As for accuracy, the only significant difference concerned the higher sensitivity of our animal test versus the RBMT belonging test. Conclusions: The clock and the animal tests showed similar specificity, but higher sensitivity than the RBMT subtests.7011721(1994) Diagnosis and Statistical Manual of Mental Disorders (4th Ed.): Text Revised, , American Psychiatric Association, Washington, DC: APATulving, E., Multiple memory systems and consciousness (1987) Human Neurobiol, 6, pp. 67-80Dubois, B., Prodromal Alzheimer's disease: A more useful concept than mild cognitive impairment? (2000) Curr Op Neurol, 13, pp. 367-369Ingvar, D.H., Memory of the future: An essay on the temporal organization of conscious awareness (1985) Human Neurobiol, 4, pp. 127-136Jones, S., Livner, A., Bäckman, L., Patterns of prospective and retrospective memory impairment in preclinical Alzheimer's disease (2006) Neuropsychology, 20, pp. 144-152Martins, S.P., Damasceno, B.P., Prospective and retrospective memory in mild Alzheimers disease (2008) Arq Neuropsiquiatr, 66, pp. 318-322Karantzoulis, S., Troyer, A.K., Rich, J.B., Prospective memory in amnestic mild cognitive impairment (2009) J Internat Neuropsychol Soc, 15, pp. 407-415Einstein, G.O., McDaniel, M.A., Richardson, S.L., Guynn, M.J., Aging and prospective memory: Examining the influences of self-initiation retrieval processes. Learning, memory, and cognition (1995) J Exp Psychol, 21, pp. 996-1007Einstein, G.O., McDaniel, M.A., Normal aging and prospective memory. Learning, memory, and cognition (1990) J Exp Psychol, 16, pp. 717-726Wechsler, D., (1997) Wechsler Memory Scale, , San Antonio, TX: The Psychological CorporationWilson, B.A., The development and validation of a test of everyday memory behavior (1989) J Clin Exp Psychol, 11, pp. 855-887Yassuda, M.S., Flaks, M.K., Viola, L.F., Psychometric characteristics of the Rivermead Behavioral Memory Test (RBMT) as an early detection instrument for dementia and mild cognitive impairment in Brazil (2010) Internat Psychogeriatrics, 22, pp. 1003-1011McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D.L., Stadlan, E.M., Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Healthand Human Services Task Force on Alzheimer's disease (1984) Neurology, 34, pp. 939-944Morris, J.C., The clinical dementia rating (CDR): Current version and scoring rules (1993) Neurology, 43, pp. 2412-2414Brucki, S.M.D., Nitrini, R., Caramelli, P., Bertolucci, P.H.F., Okamoto, I.H., Sugestões para o uso do mini-exame do estado mental no Brasil (2003) Arq Neuropsiquiatr, 61, pp. 777-781McDaniel, M.A., Einstein, G.O., (2007) Prospective Memory: An Overview and Synthesis of An Emerging Field, , Los Angeles, CA: Sage PublicationsSpreen, O., Strauss, E., (1998) A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary, , Oxford: Oxford University PressAlexopoulos, G.S., Abrams, R.C., Youn, R.C., Shamoian, C.A., Cornell Scale for depression in dementia (1988) Biol Psychiatry, 23, pp. 271-284Jones-Gotman, M., Zatorre, R.J., Olivier, A., Learning and retention of words and designs following excision from medial or lateral temporal-lobe structures (1997) Neuropsychology, 35, pp. 963-973SAS System for Windows (Statistical Analysis System), Version 9.1.3, pp. 2002-2003. , Cary, NC: SAS Institute, IncPorto, C.S., Fichman, H.C., Caramelli, P., Bahia, V.S., Nitrini, R., Brazilian version of the Mattis Dementia Rating Scale: Diagnosis of mild dementia in Alzheimer's disease (2003) Arq Neuropsiquiatr, 61, pp. 339-345Small, S.A., Stern, Y., Tang, M., Maueux, R., Selective decline in memory function among healthy elderly (1999) Neurology, 52, pp. 1392-1396Huppert, F.A., Beardsall, L., Prospective memory impairment as an early indicator of dementia (1993) J Clin Exp Neuropsychol, 15, pp. 805-821Maylor, E.A., Smith, G., Sala, S.D., Logie, R.H., Prospective and retrospective memory in normal ageing and dementia: A questionnaire study (2000) Memory, 8, pp. 311-321Duchek, J.M., Balota, D.A., Cortese, M., Prospective memory and apolipotrotein E in healthy aging and early stage Alzheimer's disease (2006) Neuropsychology, 20, pp. 633-64

Bickerstaff's Encephalitis, Guillain-barré Syndrome And Idiopathic Intracranial Hypertension: Are They Related Conditions?

[No abstract available]663 B744746Hughes, R.A., Cornblath, D.R., Guillain-Barré syndrome. (2005) Lancet, 366, pp. 1653-1666Overell, J.R., Willison, H.J., Recent developments in Miller Fisher syndrome and related disorders (2005) Curr Opin Neurol, 18, pp. 562-566Odaka, M., Yuki, N., Yamada, M., Bickerstaff's brainstem encephalitis: Clinical features of 62 cases and a subgroup associated with Guillain-Barré syndrome (2003) Brain, 126, pp. 2279-2290Ball, A.K., Clarke, C.E., Idiopathic intracranial hypertension (2006) Lancet Neurol, 5, pp. 433-442Walker, R.W., Idiopathic intracranial hypertension: Any light on the mechanism of the raised pressure? (2001) J Neurol Neurosurg Psychiatry, 71, pp. 1-5Weiss, G.B., Bajwa, Z.H., Mehler, M.F., Co-occurrence of pseudotumor cerebri and Guillain-Barré syndrome in an adult (1991) Neurology, 41, pp. 603-604Ropper, A.H., Marmarou, A., Mechanism of pseudotumor in Guillain-Barré syndrome (1984) Arch Neurol, 41, pp. 259-261Pulitanò, S., Viola, L., Genovese, O., Miller-Fisher syndrome mimicking intracranial hypertension following head trauma (2005) Childs Nerv Syst, 21, pp. 473-476Fisher, M., An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia) (1956) N Engl J Med, 255, pp. 57-65Bickerstaff, E.R., Brain-stem encephalitisfurther observations on a grave syndrome with benign prognosis (1957) Br Med J, 1, pp. 1384-1387Al-Din, A.N., The nosological position of the ophthalmoplegia, ataxia and areflexia syndrome: "the spectrum hypothesis (1987) Acta Neurol Scand, 75, pp. 287-294Chiba, A., Kusunoki, S., Obata, H., Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain-Barré syndrome: Clinical and immunohistochemical studies (1993) Neurology, 43, pp. 1911-1917Nagaoka, U., Kato, T., Kurita, K., Cranial nerve enhancement on three-dimensional MRI in Miller Fisher syndrome (1996) Neurology, 47, pp. 1601-1602Kornberg, A.J., Pestronk, A., Blume, G.M., Selective staining of the cerebellar molecular layer by serum IgG in Miller Fisher and related syndromes (1996) Neurology, 47, pp. 1317-1320Lo, Y.L., Chan, L.L., Pan, A., Ratnagopal, P., Acute ophthalmoparesis in the anti-GQ1b antibody syndrome: Electrophysiological evidence of neuromuscular transmission defect in the orbicularis oculi (2004) J Neurol Neurosurg Psychiatry, 75, pp. 436-440Yuki, N., Koga, M., Bacterial infections in Guillain-Barré and Fisher syndromes (2006) Curr Opin Neurol, 19, pp. 451-457Kwon, H.M., Hong, Y.H., Sung, J.J., A case of Bickerstaff's brainstem encephalitisthe evidence of cerebellum involvement by SPM analysis using PET (2006) Clin Neurol Neurosurg, 108, pp. 418-420Urushitani, M., Udaka, F., Kameyama, M., Miller Fisher-Guillain-Barré overlap syndrome with enhancing lesions in the spinocerebellar tracts (1995) J Neurol Neurosurg Psychiatry, 58, pp. 241-243Ogawara, K., Kuwabara, S., Yuki, N., Fisher syndrome or Bickerstaff brainstem encephalitis? Anti-GQ1b IgG antibody syndrome involving both the peripheral and central nervous systems (2002) Muscle Nerve, 26, pp. 845-849Overell, J.R., Hsieh, S.T., Odaka, M., Treatment for Fisher syndrome, Bickerstaff's brainstem encephalitis and related disorders (2007) Cochrane Database Syst Rev, 1. , CD00476

The immunomodulator glatiramer acetate influences spinal motoneuron plasticity during the course of multiple sclerosis in an animal model

The immunomodulador glatiramer acetate (GA) has been shown to significantly reduce the severity of symptoms during the course of multiple sclerosis and in its animal model - experimental autoimmune encephalomyelitis (EAE). Since GA may influence the response of non-neuronal cells in the spinal cord, it is possible that, to some extent, this drug affects the synaptic changes induced during the exacerbation of EAE. In the present study, we investigated whether GA has a positive influence on the loss of inputs to the motoneurons during the course of EAE in rats. Lewis rats were subjected to EAE associated with GA or placebo treatment. The animals were sacrificed after 15 days of treatment and the spinal cords processed for immunohistochemical analysis and transmission electron microscopy. A correlation between the synaptic changes and glial activation was obtained by performing labeling of synaptophysin and glial fibrillary acidic protein using immunohistochemical analysis. Ultrastructural analysis of the terminals apposed to alpha motoneurons was also performed by electron transmission microscopy. Interestingly, although the GA treatment preserved synaptophysin labeling, it did not significantly reduce the glial reaction, indicating that inflammatory activity was still present. Also, ultrastructural analysis showed that GA treatment significantly prevented retraction of both F and S type terminals compared to placebo. The present results indicate that the immunomodulator GA has an influence on the stability of nerve terminals in the spinal cord, which in turn may contribute to its neuroprotective effects during the course of multiple sclerosis.17918

Whipple's Disease With Neurological Manifestations: Case Report

Whipple's disease (WD) is an uncommon multisystem condition caused by the bacillus Tropheryma whipplei. Central nervous system involvement is a classical feature of the disease observed in 20 to 40% of the patients. We report the case of a 62 yeards old man with WD that developed neurological manifestations during its course, and discuss the most usual signs and symptoms focusing on recent diagnostic criteria and novel treatment regimens.622 A342346Whipple, G.H., A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues (1907) Johns Hopkins Hosp Bull, 18, pp. 382-391Marth, T., Raoult, D., Whipple's disease (2003) Lancet, 36, pp. 239-246Gerard, A., Sarrot-Reynauld, F., Liozon, E., Neurologic presentation of Whipple disease: Report of 12 cases and review of the literature (2002) Medicine (Baltimore), 81, pp. 443-457Brown, A.P., Lane, J.C., Murayama, S., Vollmer, D.G., Whipple's disease presenting with isolated neurological symptoms: Case report (1990) J Neurosurg, 73, pp. 623-627Bostwick, D.G., Bensch, K.G., Burke, J.S., Whipple's disease presenting as aortic insufficiency (1981) N Engl J Med, 305, pp. 995-998Raoult, D., A febrile, blood culture-negative endocarditis (1999) Ann Intern Med, 131, pp. 144-146Chan, R.Y., Yannuzzi, L.A., Foster, C.S., Ocular Whipple's disease: Earlier definitive diagnosis (2001) Ophthalmology, 108, pp. 2225-2231Louis, E.D., Lynch, T., Kaufmann, P., Fahn, S., Odel, J., Diagnostic guidelines in central nervous system Whipple's disease (1996) Ann Neurol, 40, pp. 561-568Sieracki, J.C., Whipple's disease: Observations on systemic involvement (1958) Amer Med Asso Arch Pathol, 66, pp. 464-467Anderson, M., Neurology of Whipple's disease (2000) J Neurol Neurosurg Psychiatry, 68, pp. 2-5De Coene, B., Gilliard, C., Indekeu, P., Whipple's disease confined to the central nervous system (1996) Neuroradiology, 38, pp. 325-327Verhagen, W.I.M., Huygen, P.L.M., Dalman, J.E., Schuurmans, M.M.J., Whipple's disease and the central nervous system: A case report and a review of the literature (1996) Clin Neurol Neurosurg, 98, pp. 299-304Feldman, M., Hendler, R.S., Morrison, E.B., Acute meningoencephalitis after withdrawal of antibiotics in Whipple's disease (1980) Ann Intern Med, 93, pp. 709-711Schwartz, M.A., Selhorst, J.B., Ochs, A.L., Oculomasticatory myorhythmia: A unique movement disorder occurring in Whipple's disease (1986) Ann Neurol, 20, pp. 677-683Manzel, K., Tranel, D., Cooper, G., Cognitive and behavioral abnormalities in a case of central nervous system Whipple disease (2000) Arch Neurol, 57, pp. 399-403Halperin, J.J., Landis, D.M., Kleinman, G.M., Whipple's disease of the nervous system (1982) Neurology, 32, pp. 612-617Feurle, G.E., Volk, B., Waldherr, R., Cerebral Whipple's disease with negative jejunal histology (1979) N Engl J Med, 300, pp. 907-908Madoule, P., Ciaudio-Lacroix, C., Halimi, P., Osteoarticular lesions in Whipple's disease, a propos of a destructive form and review of the literature (1985) J Radiol, 66, pp. 345-350Brändle, M., Ammann, P., Spinas, G.A., Relapsing Whipple's disease presenting with hypopituitarism (1999) Clin Endocrinol, 50, pp. 399-403Topper, R., Gartung, C., Block, F., Neurologic complications in inflammatory bowel diseases (2002) Nervenarzt, 73, pp. 489-499Clarke, C.E., Falope, Z.F., Abdelhadi, H.A., Cervical myelopathy caused by Whipple's disease (1998) Neurology, 50, pp. 1505-1506Ramzan, N.N., Loftus, E., Burgart, L.J., Diagnosis and monitoring of Whipple disease by polymerase chain reaction (1997) Ann Intern Med, 126, pp. 520-527Von Herbay, A., Ditton, H.J., Scuhmacher, F., Whipple's disease: Staging and monitoring by cytology and polymerase chain reaction analysis of cerebrospinal fluid (1997) Gastroenterology, 113, pp. 434-441Kremer, S., Besson, G., Bonaz, B., Pasquier, B., Le Bas, J.F., Grand, S., Diffuse lesions in the CNS revealed by MR imaging in a case of Whipple disease (2001) Am J Neuroradiol, 22, pp. 493-495Romanul, F.C., Radvany, J., Rosales, R.K., Whipple's disease confined to the brain: A case studied clinically and pathologically (1977) J Neurol Neurosurg Psychiatry, 40, pp. 901-909Thompson, D.G., Leidingham, J.M., Howard, A.J., Brown, C.L., Meningitis in Whipple's disease (1978) BMJ, 2, pp. 14-15Feurle, G.E., Marth, T., An evaluation of antimicrobial treatment for Whipple's disease: Tetracycline versus trimethoprim-sulfamethoxazole (1994) Dig Dis Sci, 39, pp. 1642-1648Misbah, S.A., Mapstone, N.P., Whipple's disease revisited (2000) J Clin Pathol, 53, pp. 750-755Schnider, P.J., Reisinger, E.C., Berger, T., Krejs, G.J., Auff, E., Treatment guidelines in central nervous system Whipple's disease (1997) Ann Neurol, 41, pp. 561-56

Global, regional, and national levels of maternal mortality, 1990�2015: a systematic analysis for the Global Burden of Disease Study 2015

Background In transitioning from the Millennium Development Goal to the Sustainable Development Goal era, it is imperative to comprehensively assess progress toward reducing maternal mortality to identify areas of success, remaining challenges, and frame policy discussions. We aimed to quantify maternal mortality throughout the world by underlying cause and age from 1990 to 2015. Methods We estimated maternal mortality at the global, regional, and national levels from 1990 to 2015 for ages 10�54 years by systematically compiling and processing all available data sources from 186 of 195 countries and territories, 11 of which were analysed at the subnational level. We quantified eight underlying causes of maternal death and four timing categories, improving estimation methods since GBD 2013 for adult all-cause mortality, HIV-related maternal mortality, and late maternal death. Secondary analyses then allowed systematic examination of drivers of trends, including the relation between maternal mortality and coverage of specific reproductive health-care services as well as assessment of observed versus expected maternal mortality as a function of Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Findings Only ten countries achieved MDG 5, but 122 of 195 countries have already met SDG 3.1. Geographical disparities widened between 1990 and 2015 and, in 2015, 24 countries still had a maternal mortality ratio greater than 400. The proportion of all maternal deaths occurring in the bottom two SDI quintiles, where haemorrhage is the dominant cause of maternal death, increased from roughly 68 in 1990 to more than 80 in 2015. The middle SDI quintile improved the most from 1990 to 2015, but also has the most complicated causal profile. Maternal mortality in the highest SDI quintile is mostly due to other direct maternal disorders, indirect maternal disorders, and abortion, ectopic pregnancy, and/or miscarriage. Historical patterns suggest achievement of SDG 3.1 will require 91 coverage of one antenatal care visit, 78 of four antenatal care visits, 81 of in-facility delivery, and 87 of skilled birth attendance. Interpretation Several challenges to improving reproductive health lie ahead in the SDG era. Countries should establish or renew systems for collection and timely dissemination of health data; expand coverage and improve quality of family planning services, including access to contraception and safe abortion to address high adolescent fertility; invest in improving health system capacity, including coverage of routine reproductive health care and of more advanced obstetric care�including EmOC; adapt health systems and data collection systems to monitor and reverse the increase in indirect, other direct, and late maternal deaths, especially in high SDI locations; and examine their own performance with respect to their SDI level, using that information to formulate strategies to improve performance and ensure optimum reproductive health of their population. Funding Bill & Melinda Gates Foundation. © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licens

Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990�2015: a systematic analysis for the Global Burden of Disease Study 2015

Background Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) 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 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. Findings Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2·9 years (95 uncertainty interval 2·9�3·0) for men and 3·5 years (3·4�3·7) for women, while HALE at age 65 years improved by 0·85 years (0·78�0·92) and 1·2 years (1·1�1·3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. Interpretation Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum. Funding Bill & Melinda Gates Foundation. © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licens

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990�2015: a systematic analysis for the Global Burden of Disease Study 2015

Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors�the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25 over the same period. All risks jointly evaluated in 2015 accounted for 57·8 (95 CI 56·6�58·8) of global deaths and 41·2 (39·8�42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million 192·7 million to 231·1 million global DALYs), smoking (148·6 million 134·2 million to 163·1 million), high fasting plasma glucose (143·1 million 125·1 million to 163·5 million), high BMI (120·1 million 83·8 million to 158·4 million), childhood undernutrition (113·3 million 103·9 million to 123·4 million), ambient particulate matter (103·1 million 90·8 million to 115·1 million), high total cholesterol (88·7 million 74·6 million to 105·7 million), household air pollution (85·6 million 66·7 million to 106·1 million), alcohol use (85·0 million 77·2 million to 93·0 million), and diets high in sodium (83·0 million 49·3 million to 127·5 million). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation. © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licens