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International audience; BACKGROUND: Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex. METHODS: We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions. FINDINGS: In 2010, there were 52*8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24*9% of deaths worldwide in 2010, down from 15*9 million (34*1%) of 46*5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2*5 to 1*4 million), lower respiratory infections (from 3*4 to 2*8 million), neonatal disorders (from 3*1 to 2*2 million), measles (from 0*63 to 0*13 million), and tetanus (from 0*27 to 0*06 million). Deaths from HIV/AIDS increased from 0*30 million in 1990 to 1*5 million in 2010, reaching a peak of 1*7 million in 2006. Malaria mortality also rose by an estimated 19*9% since 1990 to 1*17 million deaths in 2010. Tuberculosis killed 1*2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34*5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1*5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12*9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1*3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5*1 million deaths) was marginally higher in 2010 (9*6%) compared with two decades earlier (8*8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1*3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted. INTERPRETATION: Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis. FUNDING: Bill & Melinda Gates Foundation.

To demonstrate the benefit of an institutionally implemented glucose control intervention based on serum and plasma glucose values in the acute inpatient setting.In a retrospective analysis, all serum and plasma glucose values from the laboratory information system database from 1999 through 2005 were used to assess implementation of 2 new hospital-wide intravenous and subcutaneous protocols aimed at lowering blood glucose values without increasing the number of hypoglycemic events. In our analysis, we used both a per-patient hyperglycemic index (HGI), an area-under-the-curve analysis, and hospital-wide geometric mean blood glucose to assess glucose control. Bedside capillary blood glucose measurements were not included.More than 630,000 serum and plasma glucose results were available for analysis. The percentage of results above the protocol target of 180 mg/dL decreased from 16.4% before the intervention to 10.0% after the intervention (P.00001), and we found no change in the proportion of "critical" hypoglycemic results (50 mg/dL). The hospital-wide geometric mean decreased significantly and coincided with a significant decrease in the fraction of patients with poor glucose control (based on the HGI) from 27.6% to 18.7% (P.00001). The geometric mean blood glucose was found to be an excellent marker for the HGI (r2 = 0.99).We are the first to report improvements in glucose control over an extended period with use of both hospital-wide intravenous and subcutaneous insulin protocols in an academic hospital setting. Furthermore, hospital-wide mean blood glucose levels are excellent surrogates for the more comprehensive calculation of per-patient HGI.

Background Anaemia is associated with increased maternal and neonatal mortality, with young children most at risk of developing long-term ramifications. Most previous studies have been geographically limited with little detail about severity or aetiology. In this analysis, we completed the most comprehensive survey of anaemia burden to date. Methods Using publicly available data, we estimated mild, moderate, and severe anaemia in 1990 and 2010 for 187 countries, both sexes, and 20 age groups. We then performed cause-specific attribution to 17 conditions using data and resources of the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2010. Findings Global anaemia prevalence in 2010 was 32·9%, causing 68·36 million years lived with disability (95% CI 40·98–107·54 million; 8·8% of the total for all conditions, 95% CI 6·3–11·7). Prevalence dropped for both sexes from 1990 to 2010, though more so for males. Females' prevalence was higher in most regions and age groups. South Asia and central, west, and east sub-Saharan Africa had the highest burden, while east, southeast, and south Asia saw the greatest reductions. Ten different conditions were among the top three in prevalence, depending on the region. Malaria, schistosomiasis, and chronic kidney disease-related anaemia were the only conditions to increase in prevalence. Haemoglobinopathies made significant contributions to the anaemia burden in both sexes, most regions, and all time periods. Burden was highest in children under 5 years old, the only age groups with negative trends from 1990 to 2010. Interpretation Anaemia is a heterogeneous and complex condition. Despite significant progress, many challenges remain. Regional differences remain stark, some conditions are growing as a proportion of overall anaemia, the gender gap is widening, and the total disease burden remains high. Worryingly, young children, the most vulnerable group, appear to be doing worse over the past 20 years. Targeted surveillance and intervention in high-risk populations should be a greater priority. Funding Funding for GBD 2010 was provided by the Bill & Melinda Gates Foundation.

A multiple perturbation method for the treatment of molecular reactivity is generalized to describe the simultaneous interaction of a molecule containing several reactive sites with a second molecule and a point charge. The modification of the reactivity properties of the main molecule by electrostatic interaction, polarization, dispersion and correlation corrections due to the presence of the second molecule, is identified from the effect of these corrections on the interaction energy with the point charge. The decomposition of interaction energies inherent to the perturbation expansion facilities this analysis. The method is applied to a simple molecule containing two reactive sites (formyl flouride — HCOF), interacting with HF at hydrogen-bond distances. The results are very good agreement with super-molecule LCAO SCF calculations with gaussian basis functions and indicate that the redistribution of the electron density caused by the interaction of the two molecules is adequately represented by the perturbation method.

Both ab initio and INDO molecular orbital calculations on histamine show that the histamine N(3)H tautomer is preferred for the monocationic form, whereas in the neutral state the N(1)H tautomer is favored. This implies that upon neutralization of the protonated histamine which is predominant in the neutral aqueous solution the tautomeric shift occurs from the N(3)H to the N(1)H form. Although the total electronic energy term makes the N(1)H tautomer of the monocation more favorable, it is the nuclear repulsion term that results in the N(3)H tautomer for the monocation being more stable. The tautomeric energy difference for both the neutral and protonated histamines is independent of the side chain conformations.

It is shown that an electrophilic attack on the ring nitrogen in pyrrole or tryptamine produces an electron charge redistribution that is qualitatively different from the redistribution caused by an attack on the oxygen in furan. The electrophilic attacks are represented theoretically as interactions with a positive point charge and calculated by an ab-initio LCAO-SCF method with gaussian basis sets. Results show that an attacked nitrogen responds to the perturbation by moving electronic charge to the adjacent carbons whereas oxygen retains most of the charge polarized by the interaction. The nitrogen also acts as a charge transducer in other systems that are structurally very different. As a consequence of the charge redistribution, the comparative susceptibility of various sites in the heterocyclic molecules to an electrophilic attack may also depend on the response of the molecule to a prior attack on the heteroatom. The results indicate the need for dynamical reactivity considerations which reflect the variability in the molecular response to an incipient attack and the possibility that enhanced reactivity can be induced at certain sites by this response.