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

Activity-dependent degeneration of axotomized neuromuscular synapses in Wld(S) mice

AbstractActivity and disuse of synapses are thought to influence progression of several neurodegenerative diseases in which synaptic degeneration is an early sign. Here we tested whether stimulation or disuse renders neuromuscular synapses more or less vulnerable to degeneration, using axotomy as a robust trigger. We took advantage of the slow synaptic degeneration phenotype of axotomized neuromuscular junctions in flexor digitorum brevis (FDB) and deep lumbrical (DL) muscles of Wallerian degeneration-Slow (WldS) mutant mice. First, we maintained ex vivo FDB and DL nerve-muscle explants at 32°C for up to 48h. About 90% of fibers from WldS mice remained innervated, compared with about 36% in wild-type muscles at the 24-h checkpoint. Periodic high-frequency nerve stimulation (100Hz: 1s/100s) reduced synaptic protection in WldS preparations by about 50%. This effect was abolished in reduced Ca2+ solutions. Next, we assayed FDB and DL innervation after 7days of complete tetrodotoxin (TTX)-block of sciatic nerve conduction in vivo, followed by tibial nerve axotomy. Five days later, only about 9% of motor endplates remained innervated in the paralyzed muscles, compared with about 50% in 5day-axotomized muscles from saline-control-treated WldS mice with no conditioning nerve block. Finally, we gave mice access to running wheels for up to 4weeks prior to axotomy. Surprisingly, exercising WldS mice ad libitum for 4weeks increased about twofold the amount of subsequent axotomy-induced synaptic degeneration. Together, the data suggest that vulnerability of mature neuromuscular synapses to axotomy, a potent neurodegenerative trigger, may be enhanced bimodally, either by disuse or by hyperactivity

PGAA/NAA analysis with the Lawrence Berkeley National Laboratory (LBNL) D+D neutron generator

Prompt Gamma Activation Analysis (PGAA) at nuclear reactors has undergone a renaissance with the advent of modern spectroscopy equipment, development of a precise database for PGAA analysis, and the development of guided neutron beams and remote target facilities far from the reactor core. PGAA at these facilities is complemented by short-lived Neutron Activation Analysis (NAA) because decay gamma rays are observed either simultaneously with prompt gamma rays or separately if the neutron beam is chopped. Activities with half-lives as short as 1 ms can now be analyzed with NAA. Sensitivity of less than 0.1 mg/g of any element except Helium has been achieved with a 106 ncm-2s-1 thermal neutron beam. This kind of analysis has so far been limited to a handful of reactor facilities around the world. At Lawrence Berkeley National Laboratory (LBNL) we are developing a PGAA/NAA analysis system based on a compact, low power, >4'109 n/s D+D (En>2.5 MeV) neutron generator. The generator creates minimal gamma-ray background so detectors can be placed close to the target where the neutron flux is comparable to the guided neutron beam at a reactor. A D+D generator requires less thickness of moderator to thermalize neutrons than a conventional D+T (En>14 MeV) generator and eliminates the environmental and political concerns raised by using tritium. This paper discusses our initial PGAA/NAA experimental results for the LBNL neutron generator and future plans to develop reactor-quality PGAA/NAA analysis in the laboratory

PGAA/NAA analysis with the Lawrence Berkeley National Laboratory (LBNL) D+D neutron generator

Prompt Gamma Activation Analysis (PGAA) at nuclear reactors has undergone a renaissance with the advent of modern spectroscopy equipment, development of a precise database for PGAA analysis, and the development of guided neutron beams and remote target facilities far from the reactor core. PGAA at these facilities is complemented by short-lived Neutron Activation Analysis (NAA) because decay gamma rays are observed either simultaneously with prompt gamma rays or separately if the neutron beam is chopped. Activities with half-lives as short as 1 ms can now be analyzed with NAA. Sensitivity of less than 0.1 mg/g of any element except Helium has been achieved with a 106 ncm-2s-1 thermal neutron beam. This kind of analysis has so far been limited to a handful of reactor facilities around the world. At Lawrence Berkeley National Laboratory (LBNL) we are developing a PGAA/NAA analysis system based on a compact, low power, >4'109 n/s D+D (En>2.5 MeV) neutron generator. The generator creates minimal gamma-ray background so detectors can be placed close to the target where the neutron flux is comparable to the guided neutron beam at a reactor. A D+D generator requires less thickness of moderator to thermalize neutrons than a conventional D+T (En>14 MeV) generator and eliminates the environmental and political concerns raised by using tritium. This paper discusses our initial PGAA/NAA experimental results for the LBNL neutron generator and future plans to develop reactor-quality PGAA/NAA analysis in the laboratory