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

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias

International nosocomial infection control consortium (INICC) report, data summary of 36 countries, for 2004-2009

The results of a surveillance study conducted by the International Nosocomial Infection Control Consortium (INICC) from January 2004 through December 2009 in 422 intensive care units (ICUs) of 36 countries in Latin America, Asia, Africa, and Europe are reported. During the 6-year study period, using Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN; formerly the National Nosocomial Infection Surveillance system [NNIS]) definitions for device-associated health care-associated infections, we gathered prospective data from 313,008 patients hospitalized in the consortium's ICUs for an aggregate of 2,194,897 ICU bed-days. Despite the fact that the use of devices in the developing countries' ICUs was remarkably similar to that reported in US ICUs in the CDC's NHSN, rates of device-associated nosocomial infection were significantly higher in the ICUs of the INICC hospitals; the pooled rate of central line-associated bloodstream infection in the INICC ICUs of 6.8 per 1,000 central line-days was more than 3-fold higher than the 2.0 per 1,000 central line-days reported in comparable US ICUs. The overall rate of ventilator-associated pneumonia also was far higher (15.8 vs 3.3 per 1,000 ventilator-days), as was the rate of catheter-associated urinary tract infection (6.3 vs. 3.3 per 1,000 catheter-days). Notably, the frequencies of resistance of Pseudomonas aeruginosa isolates to imipenem (47.2% vs 23.0%), Klebsiella pneumoniae isolates to ceftazidime (76.3% vs 27.1%), Escherichia coli isolates to ceftazidime (66.7% vs 8.1%), Staphylococcus aureus isolates to methicillin (84.4% vs 56.8%), were also higher in the consortium's ICUs, and the crude unadjusted excess mortalities of device-related infections ranged from 7.3% (for catheter-associated urinary tract infection) to 15.2% (for ventilator-associated pneumonia). Copyright © 2012 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved

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

MATCHING LOCAL COMPOSITION AND MECHANICAL PROPERTY ANISOTROPY OF PREOXIZED (Ni, Pt)Al BOND COATS AFTER THERMAL CYCLING TESTS

Pt-modified nickel aluminide, B2 (Ni,Pt)Al, coatings are used to protect the surface of turbine airfoils against oxidation [1]. However, the lack of ductility of these systems presents a drawback in their performance. At high temperatures several elements diffuse from the superalloy substrate and become incorporated into the B2 phase, which can modify its mechanical properties. This diffusion process also results in a distribution of elements throughout the coating that can change from grain to grain. Few reports on the local, micromechanical properties of B2 (Ni,Pt)Al coatings measured by nanoindentation, taking into account crystal orientation, have been published. No anisotropy effect of elastic modulus in the B2 (Ni,Pt)Al was observed by Durst et al. [2], but their finding remains to be understood, and the effect of local chemical composition is yet to be thoroughly explored. In this work, coupons of Rene-N5 superalloy coated with a B2 (Ni,Pt)Al bond coat were pre-oxidized at different temperatures and oxygen partial pressures (pO2) in order to generate a protective α-Al2O3 scale. An yttria-stabilized zirconia (7YSZ) top-coat layer was subsequently deposited by EB-PVD to complete the thermal barrier coating (TBCs). Finally, the TBCs were subjected to thermal cycling tests, during which the (Ni,Pt)Al was observed to transform from pure B2 to a combination of L10 (martensitic), L12 (ordered fcc), and B2 (ordered bcc) phases. Electron backscattering diffraction (EBSD) was used to identify the crystal orientation of the different phases. The mechanical properties of grains oriented in the [001], [101], and [111] directions were measured by nanoindentation with two different indenter geometries, Berkovich and cono-spherical. No anisotropy of mechanical properties was found using the Berkovich indenter, whereas slight differences were observed with the cono-spherical indenter. Moreover, strong differences in the elastic limit were observed when measuring with the cono-spherical within the same grain, which is attributed to differences in the local chemical composition. Finally, the mechanical properties of the L10 and L12 phases are presented and discussed. References: [1] J. Esslinger and E.E. Affeldt, Transactions of the ASME, Journal of Engineering for Gas Turbines and Power, 121 (1998): 687-690. [2] K. Durst, O. Franke and M. Göken, Proceedings Superalloys (2004): 467-476

FAILURE ANALYSIS OF PRE-OXIDIZED ReneN5/ β-(Ni,Pt)Al/7YSZ EB-PVD THERMAL BARRIER COATINGS

Nowadays Pt-modified nickel aluminides, (Ni,Pt)Al, are highly used as alumina-forming alloys in the aerospace industry. These alloys have been studied to improve the lifetime of the thermal barrier coating systems (TBCs) when they are exposed to thermal-cyclic tests [1-3]. The use of (Ni,Pt)Al alloy as bond coat (BC) is to provide oxidation protection of the Ni-base superalloy (SA) used as a substrate of hot-section turbine blades. BCs act as an aluminum reservoir that leads to the formation of a thermally grown oxide (TGO). The TGO improves the adherence between the metal and a ceramic top coat (TC), which provides thermal insulation during the operation of these components. The aim of the present study is to evaluate the effect of the pre-oxidation treatments before TC deposition on the thermal-cyclic life of ReneN5/(Ni,Pt)Al/7YSZ TBCs. The effect of different oxygen partial pressures (pO2= 2.1x10-1, 1.05x10-1, 1x10-5 and 1x10-9 atm) pre-oxidation treatments were evaluated and compared to regular TBCs after EB-PVD TC deposition in “as-coated” conditions. A post-mortem analysis of the samples was also carried out after 1 h thermal-cyclic testing at 1100ºC to study the intrinsic mechanisms associated to the failure. Samples pre-oxidized with a combination of Argon-Gettered atmosphere (pO2=1x10-9 atm) showed the highest performance in average (1550 cycles to failure). For all the different pre-oxidation conditions, the failure occurred majority along the TC/TGO interface. Mapping of grain orientation determined by EBSD combined with nanoindentation tests were carried out to evaluate anisotropic effects and structural characterization with their mechanical properties after thermal-cyclic tests. Efforts are currently being done to link the failure of the samples to the microstructural characteristics. For instance a continuous layer of martensitic phase, L10, along the bond coat has been observed after failure for the thermal-cyclic tested samples. The reversible L10↔β phase transformation and the reaction β γ' are the main phenomena that take place during thermal cycling and results from the BC aluminum depletion due to TGO formation and its diffusion to the SA [4-6]. Moreover, cracks have been identified in the L10/γ' grains interface. Finally, it must be pointed out that the non-pre-oxidized TBCs have shown a mixed zone in the TGO, which consists on a region where zirconia particles are dispersed in the TGO matrix [7]. References [1] A.G. Evans, et.al., Progress in Materials Science 46 (2001) 505 - 553. [2] V.K. Tolpygo and D.R. Clarke, Surface & Coatings Technology 200 (2005) 1276 - 1281. [3] U. Schulz, et.al., Surface & Coatings Technology 203 (2008) 160 - 170. [4] M.W. Chen, et.al., Acta Materialia (2003), 4279 - 4294. [5] J.L. Smialek and R. Giballa; Metallurgical transactions A (1983), 2143 - 2161. [6] B. Gleeson, W. Wang, S. Hayashi, D.J. Sordelet; Mater Sci Forum 2004. [7] M.J. Stiger, et.al; Metallurgical and Materials Transitions A (2007) Vol.38A 848 - 857

Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma

Abstract Background High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined. Patients and methods In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation. Results MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24–0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23–0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed. Conclusions These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials

Kinesin-II Is Required for Flagellar Sensory Transduction during Fertilization in Chlamydomonas

The assembly and maintenance of eucaryotic flagella and cilia depend on the microtubule motor, kinesin-II. This plus end-directed motor carries intraflagellar transport particles from the base to the tip of the organelle, where structural components of the axoneme are assembled. Here we test the idea that kinesin-II also is essential for signal transduction. When mating-type plus (mt+) and mating-type minus (mt−) gametes of the unicellular green alga Chlamydomonas are mixed together, binding interactions between mt+ and mt− flagellar adhesion molecules, the agglutinins, initiate a signaling pathway that leads to increases in intracellular cAMP, gamete activation, and zygote formation. A critical question in Chlamydomonas fertilization has been how agglutinin interactions are coupled to increases in intracellular cAMP. Recently, fla10 gametes with a temperature-sensitive defect in FLA10 kinesin-II were found to not form zygotes at the restrictive temperature (32°C). We found that, although the rates and extents of flagellar adhesion in fla10 gametes at 32°C are indistinguishable from wild-type gametes, the cells do not undergo gamete activation. On the other hand, fla10 gametes at 32°C regulated agglutinin location and underwent gamete fusion when the cells were incubated in dibutyryl cAMP, indicating that their capacity to respond to the cAMP signal was intact. We show that the cellular defect in the fla10 gametes at 32°C is a failure to undergo increases in cAMP during flagella adhesion. Thus, in addition to being essential for assembly and maintenance of the structural components of flagella, kinesin-II/intraflagellar transport plays a role in sensory transduction in these organelles