Studi funzionali e strutturali sul wildtype e sul mutante γM23-K della ATP sintasi di Rhodobacter capsulatus: ruolo dell'ADP e della forza protonmotiva nell'attivazione dell’enzima e nell'accoppiamento dell'idrolisi di ATP alla traslocazione protonica

Nel presente lavoro di tesi sono state messe a confronto le ATP sintasi wild-type e γM23-K in cromatofori del batterio fotosintetico Rhodobacter capsulatus sotto gli aspetti funzionale e regolatorio. Si pensava inizialmente che la mutazione, in base a studi riportati in letteratura condotti sull’omologa mutazione in E. coli, avrebbe indotto disaccoppiamento intrinseco nell’enzima. Il presente lavoro ha chiarito che il principale effetto della mutazione è un significativo aumento dell’affinità dell’enzima per l’ADP inibitorio, che ne determina il ridotto livello di ATP idrolisi e la rapidissima reinattivazione in seguito ad attivazione da forza protonmotiva. Il residuo 23 della subunità γ si trova posizionato in prossimità della regione conservata DEELSED carica negativamente della subunità β, e l’introduzione nel mutante di una ulteriore carica positiva potrebbe determinare una maggiore richiesta di energia per indurre l’apertura del sito catalitico. Un’analisi quantitativa dei dati di proton pumping condotta mediante inibizione parziale dell’idrolisi del wildtype ha inoltre mostrato come il grado di accoppiamento del mutante in condizioni standard non differisca sostanzialmente da quello del wild-type. D’altro canto, è stato recentemente osservato come un disaccoppiamento intrinseco possa venire osservato in condizioni opportune anche nel wild-type, e cioè a basse concentrazioni di ADP e Pi. Nel presente lavoro di tesi si è dimostrato come nel mutante l’osservazione del fenomeno del disaccoppiamento intrinseco sia facilitata rispetto al wild-type. È stato proprio nell’ambito delle misure condotte sul mutante che è stato possibile dimostrare per la prima volta il ruolo fondamentale della componente elettrica della forza protonmotiva nel mantenere lo stato enzimatico ad elevato accoppiamento. Tale ruolo è stato successivamente messo in luce anche nel wild-type, in parte anche grazie all’uso di inibitori specifici di F1 e di FO. Il disaccoppiamento intrinseco nel wild-type è stato ulteriormente esaminato anche nella sua dipendenza dalla rimozione di ADP e Pi; in particolare, oltre all’amina fluorescente ACMA, è stata utilizzata come sonda di ΔpH anche la 9-aminoacridina e come sonda di Δψ l’Oxonolo VI. In entrambi i casi il ruolo accoppiante di questi due ligandi è stato confermato, inoltre utilizzando la 9-aminoacridina è stato possibile calibrare il segnale di fluorescenza con salti acido-base, dando quindi una base quantitativa ai dati ottenuti. Noi riteniamo che il più probabile candidato strutturale coinvolto in questi cambiamenti di stato enzimatici sia la subunità ε, di cui è noto il coinvolgimento in processi di regolazione e in cambiamenti strutturali indotti da nucleotidi e dalla forza protonmotiva. In collaborazione con il Dipartimento di Chimica Fisica dell’Università di Friburgo è in atto un progetto per studiare i cambiamenti strutturali presumibilmente associati al disaccoppiamento intrinseco tramite FRET in singola molecola di complessi ATP-sintasici marcati con fluorofori sia sulla subunità ε che sulla subunità γ. Nell’ambito di questa tesi sono stati creati a questo fine alcuni doppi mutanti cisteinici ed è stato messo a punto un protocollo per la loro marcatura con sonde fluorescenti.

Intrinsic uncoupling in the ATP synthase of Escherichia coli. Studies on WT and ε-truncated mutants

The H+/ATP ratio in the catalysis of ATP synthase has generally been considered a fixed parameter. However, Melandri and coworkers have recently shown that, in the ATP synthase of the photosynthetic bacterium Rb.capsulatus, this ratio can significantly decrease during ATP hydrolysis when the concentration of either ADP or Pi is maintained at a low level (Turina et al., 2004). The present work has dealt with the ATP synthase of E.coli, looking for evidence of this phenomenon of intrinsic uncoupling in this organism as well. First of all, we have shown that the DCCD-sensitive ATP hydrolysis activity of E.coli internal membranes was strongly inhibited by ADP and Pi, with a half-maximal effect in the submicromolar range for ADP and at 140 µM for Pi. In contrast to this monotonic inhibition, however, the proton pumping activity of the enzyme, as estimated under the same conditions by the fluorescence quenching of the ΔpH-sensitive probe ACMA, showed a clearly biphasic progression, both for Pi, increasing from 0 up to approximately 200 µM, and for ADP, increasing from 0 up to a few µM. We have interpreted these results as indicating that the occupancy of ADP and Pi binding sites shifts the enzyme from a partially uncoupled state to a fully coupled state, and we expect that the ADP- and Pi-modulated intrinsic uncoupling is likely to be a general feature of prokaryotic ATP synthases. Moreover, the biphasicity of the proton pumping data suggested that two Pi binding sites are involved. In order to verify whether the same behaviour could be observed in the isolated enzyme, we have purified the ATP synthase of E.coli and reconstituted it into liposomes. Similarly as observed in the internal membrane preparation, in the isolated and reconstituted enzyme it was possible to observe inhibition of the hydrolytic activity by ADP and Pi (with half-maximal effects at few µM for ADP and at 400 µM for Pi) with a concomitant stimulation of proton pumping. Both the inhibition of ATP hydrolysis and the stimulation of proton pumping as a function of Pi were lost upon ADP removal by an ADP trap. These data have made it possible to conclude that the results obtained in E.coli internal membranes are not due to the artefactual interference of enzymatic activities other than the ones of the ATP synthase. In addition, data obtained with liposomes have allowed a calibration of the ACMA signal by ΔpH transitions of known extent, leading to a quantitative evaluation of the proton pumping data. Finally, we have focused our efforts on searching for a possible structural candidate involved in the phenomenon of intrinsic uncoupling. The ε-subunit of the ATP-synthase is known as an endogenous inhibitor of the hydrolysis activity of the complex and appears to undergo drastic conformational changes between a non-inhibitory form (down-state) and an inhibitory form (up-state)(Rodgers & Wilce, 2000; Gibbons et al., 2000). In addition, the results of Cipriano & Dunn (2006) indicated that the C-terminal domain of this subunit played an important role in the coupling mechanism of the pump, and those of Capaldi et al. (2001), Suzuki et al. (2003) were consistent with the down-state showing a higher hydrolysis-to-synthesis ratio than the up-state. Therefore, we decided to search for modulation of pumping efficiency in a C-terminally truncated ε mutant. A low copy number expression vector has been built, carrying an extra copy of uncC, with the aim of generating an ε-overexpressing E.coli strain in which normal levels of assembly of the mutated ATP-synthase complex would be promoted. We have then compared the ATP hydrolysis and the proton pumping activity in membranes prepared from these ε-overexpressing E.coli strains, which carried either the WT ε subunit or the ε88-stop truncated form. Both strains yielded well energized membranes. Noticeably, they showed a marked difference in the inhibition of hydrolysis by Pi, this effect being largely lost in the truncated mutant. However, pre-incubation of the mutated enzyme with ADP at low nanomolar concentrations (apparent Kd = 0.7nM) restored the hydrolysis inhibition, together with the modulation of intrinsic uncoupling by Pi, indicating that, contrary to wild-type, during membrane preparation the truncated mutant had lost the ADP bound at this high-affinity site, evidently due to a lower affinity (and/or higher release) for ADP of the mutant relative to wild type. Therefore, one of the effects of the C-terminal domain of ε appears to be to modulate the affinity of at least one of the binding sites for ADP. The lack of this domain does not appear so much to influence the modulability of coupling efficiency, but instead the extent of this modulation. At higher preincubated ADP concentrations (apparent Kd = 117nM), the only observed effects were inhibition of both hydrolysis and synthesis, providing a direct proof that two ADP-binding sites on the enzyme are involved in the inhibition of hydrolysis, of which only the one at higher affinity also modulates the coupling efficiency.

Procesos de trabajo de la Biblioteca Digital de la UNCuyo

Informe especial que hace visible los procesos de trabajo, equipamiento necesario y recurso humano interdisciplinario que lleva adelante la difusión del conocimiento científico, académico y de divulgación de la Biblioteca Digital de la Universidad Nacional de Cuyo. El video fue presentado en las Jornadas Nacionales de Bibliotecas Digitales en el 2009 con sede en la ciudad Rosario, Argentina.

Amistades paganas y persecución de los cristianos : La epístola de Bruno de Querfurt al emperador Enrique II

La carta que presentamos traducida al español fue escrita en el año 1008 por el obispo misionero Bruno de Querfurt. El destinatario era el rey sajón Enrique II (1002-1024), emperador desde el año 1014. El contexto de la epístola está marcado por los vínculos cambiantes entre diversos actores políticos. La dinastía polaca piasta había cooperado con el Imperio desde mediados del siglo x. Por otra parte, los liutizos, una confederación de pueblos eslavos paganos, se habían levantado contra las estructuras eclesiásticas e imperiales en la región del Elba en 983, en el marco de un floreciente paganismo. Sin embargo, al iniciarse el nuevo milenio, el piasta Boleslao el Bravo se había convertido en una amenaza más atemorizadora para el Imperio, debido particularmente a la expansión territorial que encabezaba. Así, el rey Enrique II pactó en el año 1003 en Quedlinburg con los liutizos frente al piasta: se sellaba una alianza entre un rey cristiano y una confederación pagana para hacer frente a otro gobernante cristiano. Bruno de Querfurt, que había dedicado su vida a la misión y recibía apoyo de Boleslao, escribió esta misiva, con el objeto de señalar las contradicciones de la alianza citada arriba

Amistades paganas y persecución de los cristianos : La epístola de Bruno de Querfurt al emperador Enrique II

La carta que presentamos traducida al español fue escrita en el año 1008 por el obispo misionero Bruno de Querfurt. El destinatario era el rey sajón Enrique II (1002-1024), emperador desde el año 1014. El contexto de la epístola está marcado por los vínculos cambiantes entre diversos actores políticos. La dinastía polaca piasta había cooperado con el Imperio desde mediados del siglo x. Por otra parte, los liutizos, una confederación de pueblos eslavos paganos, se habían levantado contra las estructuras eclesiásticas e imperiales en la región del Elba en 983, en el marco de un floreciente paganismo. Sin embargo, al iniciarse el nuevo milenio, el piasta Boleslao el Bravo se había convertido en una amenaza más atemorizadora para el Imperio, debido particularmente a la expansión territorial que encabezaba. Así, el rey Enrique II pactó en el año 1003 en Quedlinburg con los liutizos frente al piasta: se sellaba una alianza entre un rey cristiano y una confederación pagana para hacer frente a otro gobernante cristiano. Bruno de Querfurt, que había dedicado su vida a la misión y recibía apoyo de Boleslao, escribió esta misiva, con el objeto de señalar las contradicciones de la alianza citada arriba

Amistades paganas y persecución de los cristianos : La epístola de Bruno de Querfurt al emperador Enrique II

La carta que presentamos traducida al español fue escrita en el año 1008 por el obispo misionero Bruno de Querfurt. El destinatario era el rey sajón Enrique II (1002-1024), emperador desde el año 1014. El contexto de la epístola está marcado por los vínculos cambiantes entre diversos actores políticos. La dinastía polaca piasta había cooperado con el Imperio desde mediados del siglo x. Por otra parte, los liutizos, una confederación de pueblos eslavos paganos, se habían levantado contra las estructuras eclesiásticas e imperiales en la región del Elba en 983, en el marco de un floreciente paganismo. Sin embargo, al iniciarse el nuevo milenio, el piasta Boleslao el Bravo se había convertido en una amenaza más atemorizadora para el Imperio, debido particularmente a la expansión territorial que encabezaba. Así, el rey Enrique II pactó en el año 1003 en Quedlinburg con los liutizos frente al piasta: se sellaba una alianza entre un rey cristiano y una confederación pagana para hacer frente a otro gobernante cristiano. Bruno de Querfurt, que había dedicado su vida a la misión y recibía apoyo de Boleslao, escribió esta misiva, con el objeto de señalar las contradicciones de la alianza citada arriba

Deceit and Bruno Taut's Glashaus

The historical context surrounding Bruno Taut's Glashaus has been established through work of authors like Reyner Banham, Dennis Sharp and Ian Boyd-Whyte. However, these English language translations, are mostly derived from secondary sources such as Adolf Behne and Paul Scheerbart. Surprisingly, Taut's own writings largely do not feature in this prevailing account of his work. Since 1990, strong doubts have arisen about this conventional picture of Taut's Glashaus. Manfred spiedel, for instance, minimizes Paul Scheerbart's contribution to the design by arguing that Scheerbart met Taut only a few months before the construction of the Glashaus, that is, after Taut had finished his preliminary sketches. Kurt Junghanns goes further and asserts that the Glashaus design was complete beefore Taut and Scheerbart ever met. In 2005, Kai Gutschow published The Culture of Criticism: Adolf Behne and the Development of Modern Architecture in Germany, 1910 - 1914. Most startling, Gutschow asserts that Behne acts as the propagandist for the Glashaus by fabricating its link with Expressionism. This is particularly troubling because nobody contributed more to establishing the link between the Glashaus, Bruno Taut and Expressionism than Behne. As a result of this new evidence, this paper concurs that the established historical understanding of the Glashaus is flawed. By returning to Taut's own writings, a reinterpretation can be offered that strongly links the Glashaus to the Victoria regia lily and Strasbourg Cathedral. The significance of this approach is that it re-establishes Taut's own rational behind the design of the Glashaus, and thus contributes to the re-evaluation of the generally accepted histories of the Modern movement.

Natures muses in Bruno Tuat’s Glashaus

Constructed for the 1914 Werkbund Exhibition in Cologne, Germany, the Glashaus was both a seminal example of early modernist architecture and Bruno Taut’s signature building. Over time, metaphors have come to be applied to the Glashaus. Within the realm of nature these metaphors include cosmic, geological, botanic and sexual. However these metaphors, like the history of the Glashaus, are not a foregone conclusion. Recently it has been argued that the majority of our current knowledge regarding the Glashaus derives not from the perspective of Bruno Taut as the architect, but rather directly from perspective of the art critic Adolf Behne. This argument goes further and proposes that Behne’s official history of Glashaus is possibly fabricated propaganda. So, if indeed the official history of the Glashaus is questionable, then too are the natural metaphors commonly applied to the building. By revisiting Bruno Taut’s pre-1915 writings, this investigation reveals that botanic metaphors appear to have been Taut’s primary source of inspiration for the design of the Glashaus. Through the exposure of this fact, this research contributes significantly to the current debates surrounding Bruno Taut, the Glashaus and the re-evaluation of the official histories of the modern movement.

Client intentions and Bruno Taut’s Glashaus

An often overlooked aspect concerning the Glashaus is the significant influence exerted by the client in the design of the building. In an intentional endeavour to create an exhibition pavilion that best showcased their glazed products and construction technologies, the German Luxfer Prism Syndicate both commissioned and majority financed the Glashaus. It would therefore seem strange that the official histories of the Glashaus would rather record the utopian, romanticised and arguably imagined intentions of Bruno Taut as the architect, as opposed to the reality of the client’s intentions. This paper offers a reinterpretation of the Glashaus from the perspective of German Luxfer Prism Syndicate. This reinterpretation is achieved through an investigation that primarily concentrates on the glazed areas of the Glashaus where the German Luxfer Prism Syndicates products were most evident. Using the arguments initially presented by Dietrich Neumann as a foundation, this research is additionally interwoven with inquiry into diverse aspects such as patents filed by the Luxfer group of companies and a close examination of the original black and white photographs of the Glashaus. A dramatically different understanding emerges when the Glashaus is argued from the perspective of the client; an understanding that is cold, hard and commercial as opposed to utopian and romanticised. As a result, this research makes a contribution to the current debate concerning the Glashaus and the re-evaluation of the histories of the modern movement.

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010 : a systematic analysis for the Global Burden of Disease Study 2010

Background Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). Methods Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. Findings Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350 000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient −0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. Interpretation Rates of YLDs per 100 000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. Funding Bill & Melinda Gates Foundation.

The lily, client and measure of Bruno Taut’s Glashaus

The Glashaus is considered a significant exemplar of early modernist architecture and is generally accepted as having had Expressionist origins. However, current research has revealed that the design origins of this important building are not fully understood. While the historical record acknowledges the contributions of the bohemian poet Paul Scheerbart and the art critic Adolf Behne, the role of the Glashaus’ architect, Bruno Taut, has been moderated. In an attempt to rectify this situation this article proposes that the design origins of the Glashaus can be found in a strong architect-client interaction. It is argued that the Glashaus’ client, the Deutsche Luxfer Prismen Syndikat under the directorship of Frederick Keppler, exerted a significant influence on its design. In order to showcase the glazed products of Luxfer in the best manner possible, Keppler insisted that the design feature a glazed dome, electric lighting, a fountain as well as a cascade. Given the detailed stipulations of this brief, Taut had few options other than to offer interpretations of precedent that derived from the Victoria regia lily and Gothic proportioning. By expounding this architect-client relationship, this article expands our understanding of the Glashaus, and reinvigorates our understanding of this important early example of modern architecture.

The importance of the Deutsche Luxfer Prismen Syndikat, the Victoria regia lily and Gothic imitation in the design of Bruno Taut's Glashaus

Bruno Taut's Glashaus is considered a seminal example of early modernist architecture. Yet, some of the crucial factors behind the design of the Glashaus remain little understood. This PhD reveals that the Glashaus' patron, Frederick Keppler, exerted a significant influence over its design by insisting that it follow a prescriptive brief. Interpreting these rigid instructions, Taut as the architect, gained inspiration from the myths and symbols associated with the Victoria regia lily and the Gothic. This PhD therefore significantly expands the understanding of the Glashaus, and thus reinvigorates our comprehension of one of the most distinctive early examples of modern architecture.

Bruno Taut’s design inspiration for the Glashaus

As a formative exemplar of early architectural modernism, Bruno Taut’s seminal exhibition pavilion the Glashaus (literally translated Glasshouse) is logically part of the important debate of rethinking the origins of modernism. However, the historical record of Bruno Taut’s Glashaus has been primarily established by one art historian and critic. As a result the historical record of the Glashaus is significantly skewed toward a singlular notion of Expressionism and surprisingly excludes Taut’s diverse motives for the design of the building. In an effort to clarify the problematic historical record of the Glashaus, this book exposes Bruno Taut’s motives and inspirations for its design. The result is that Taut’s motives can be found in yet unacknowledged precedents like the botanical inspiration of the Victoria regia lily; the commercial interests of Frederick Keppler as the Director of the Deutche Luxfer Prismen Syndikat; and imitation that derived openly from the Gothic. The outcome is a substantial contribution to the re-evaluation of the generally accepted histories of the modern movement in architecture.

Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990–2013: Quantifying the epidemiological transition

Background The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age–sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development. Methods We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time. Findings Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6–6·6), from 65·3 years (65·0–65·6) in 1990 to 71·5 years (71·0–71·9) in 2013, HALE at birth rose by 5·4 years (4·9–5·8), from 56·9 years (54·5–59·1) to 62·3 years (59·7–64·8), total DALYs fell by 3·6% (0·3–7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6–29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non–communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries. Interpretation Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition—in which increasing sociodemographic status brings structured change in disease burden—is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5–89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.