Funding and services needed to achieve universal health coverage: applications of global, regional, and national estimates of utilisation of outpatient visits and inpatient admissions from 1990 to 2016, and unit costs from 1995 to 2016.

BACKGROUND: To inform plans to achieve universal health coverage (UHC), we estimated utilisation and unit cost of outpatient visits and inpatient admissions, did a decomposition analysis of utilisation, and estimated additional services and funds needed to meet a UHC standard for utilisation. METHODS: We collated 1175 country-years of outpatient data on utilisation from 130 countries and 2068 country-years of inpatient data from 128 countries. We did meta-regression analyses of annual visits and admissions per capita by sex, age, location, and year with DisMod-MR, a Bayesian meta-regression tool. We decomposed changes in total number of services from 1990 to 2016. We used data from 795 National Health Accounts to estimate shares of outpatient and inpatient services in total health expenditure by location and year and estimated unit costs as expenditure divided by utilisation. We identified standards of utilisation per disability-adjusted life-year and estimated additional services and funds needed. FINDINGS: In 2016, the global age-standardised outpatient utilisation rate was 5·42 visits (95% uncertainty interval [UI] 4·88-5·99) per capita and the inpatient utilisation rate was 0·10 admissions (0·09-0·11) per capita. Globally, 39·35 billion (95% UI 35·38-43·58) visits and 0·71 billion (0·65-0·77) admissions were provided in 2016. Of the 58·65% increase in visits since 1990, population growth accounted for 42·95%, population ageing for 8·09%, and higher utilisation rates for 7·63%; results for the 67·96% increase in admissions were 44·33% from population growth, 9·99% from population ageing, and 13·55% from increases in utilisation rates. 2016 unit cost estimates (in 2017 international dollars [I$]) ranged from I$2 to I$478 for visits and from I$87 to I$22 543 for admissions. The annual cost of 8·20 billion (6·24-9·95) additional visits and 0·28 billion (0·25-0·30) admissions in low-income and lower-middle income countries in 2016 was I$503·12 billion (404·35-605·98) or US$158·10 billion (126·58-189·67). INTERPRETATION: UHC plans can be based on utilisation and unit costs of current health systems and guided by standards of utilisation of outpatient visits and inpatient admissions that achieve the highest coverage of personal health services at the lowest cost. FUNDING: Bill & Melinda Gates Foundation.

Robust quantification of fish early life CO2 sensitivities via serial experimentation.

Despite the remarkable expansion of laboratory studies, robust estimates of single species CO2 sensitivities remain largely elusive. We conducted a meta-analysis of 20 CO2 exposure experiments conducted over 6 years on offspring of wild Atlantic silversides (Menidia menidia) to robustly constrain CO2 effects on early life survival and growth. We conclude that early stages of this species are generally tolerant to CO2 levels of approximately 2000 µatm, likely because they already experience these conditions on diel to seasonal timescales. Still, high CO2 conditions measurably reduced fitness in this species by significantly decreasing average embryo survival (-9%) and embryo+larval survival (-13%). Survival traits had much larger coefficients of variation (greater than 30%) than larval length or growth (3-11%). CO2 sensitivities varied seasonally and were highest at the beginning and end of the species' spawning season (April-July), likely due to the combined effects of transgenerational plasticity and maternal provisioning. Our analyses suggest that serial experimentation is a powerful, yet underused tool for robustly estimating small but true CO2 effects in fish early life stages.

Phylogenetic patterns of trait and trait plasticity evolution: Insights from amphibian embryos.

Environmental variation favors the evolution of phenotypic plasticity. For many species, we understand the costs and benefits of different phenotypes, but we lack a broad understanding of how plastic traits evolve across large clades. Using identical experiments conducted across North America, we examined prey responses to predator cues. We quantified five life-history traits and the magnitude of their plasticity for 23 amphibian species/populations (spanning three families and five genera) when exposed to no cues, crushed-egg cues, and predatory crayfish cues. Embryonic responses varied considerably among species and phylogenetic signal was common among the traits, whereas phylogenetic signal was rare for trait plasticities. Among trait-evolution models, the Ornstein-Uhlenbeck (OU) model provided the best fit or was essentially tied with Brownian motion. Using the best fitting model, evolutionary rates for plasticities were higher than traits for three life-history traits and lower for two. These data suggest that the evolution of life-history traits in amphibian embryos is more constrained by a species' position in the phylogeny than is the evolution of life history plasticities. The fact that an OU model of trait evolution was often a good fit to patterns of trait variation may indicate adaptive optima for traits and their plasticities.

Coupling among Microbial Communities, Biogeochemistry, and Mineralogy across Biogeochemical Facies.

Physical properties of sediments are commonly used to define subsurface lithofacies and these same physical properties influence subsurface microbial communities. This suggests an (unexploited) opportunity to use the spatial distribution of facies to predict spatial variation in biogeochemically relevant microbial attributes. Here, we characterize three biogeochemical facies-oxidized, reduced, and transition-within one lithofacies and elucidate relationships among facies features and microbial community biomass, richness, and composition. Consistent with previous observations of biogeochemical hotspots at environmental transition zones, we find elevated biomass within a biogeochemical facies that occurred at the transition between oxidized and reduced biogeochemical facies. Microbial richness-the number of microbial taxa-was lower within the reduced facies and was well-explained by a combination of pH and mineralogy. Null modeling revealed that microbial community composition was influenced by ecological selection imposed by redox state and mineralogy, possibly due to effects on nutrient availability or transport. As an illustrative case, we predict microbial biomass concentration across a three-dimensional spatial domain by coupling the spatial distribution of subsurface biogeochemical facies with biomass-facies relationships revealed here. We expect that merging such an approach with hydro-biogeochemical models will provide important constraints on simulated dynamics, thereby reducing uncertainty in model predictions.

The global burden of low back pain: estimates from the Global Burden of Disease 2010 study.

OBJECTIVE: To estimate the global burden of low back pain (LBP). METHODS: LBP was defined as pain in the area on the posterior aspect of the body from the lower margin of the twelfth ribs to the lower glutaeal folds with or without pain referred into one or both lower limbs that lasts for at least one day. Systematic reviews were performed of the prevalence, incidence, remission, duration, and mortality risk of LBP. Four levels of severity were identified for LBP with and without leg pain, each with their own disability weights. The disability weights were applied to prevalence values to derive the overall disability of LBP expressed as years lived with disability (YLDs). As there is no mortality from LBP, YLDs are the same as disability-adjusted life years (DALYs). RESULTS: Out of all 291 conditions studied in the Global Burden of Disease 2010 Study, LBP ranked highest in terms of disability (YLDs), and sixth in terms of overall burden (DALYs). The global point prevalence of LBP was 9.4% (95% CI 9.0 to 9.8). DALYs increased from 58.2 million (M) (95% CI 39.9M to 78.1M) in 1990 to 83.0M (95% CI 56.6M to 111.9M) in 2010. Prevalence and burden increased with age. CONCLUSIONS: LBP causes more global disability than any other condition. With the ageing population, there is an urgent need for further research to better understand LBP across different settings.

The global burden of musculoskeletal conditions for 2010: an overview of methods.

The objective of this paper is to provide an overview of methods used for estimating the burden from musculoskeletal (MSK) conditions in the Global Burden of Diseases 2010 study. It should be read in conjunction with the disease-specific MSK papers published in Annals of Rheumatic Diseases. Burden estimates (disability-adjusted life years (DALYs)) were made for five specific MSK conditions: hip and/or knee osteoarthritis (OA), low back pain (LBP), rheumatoid arthritis (RA), gout and neck pain, and an 'other MSK conditions' category. For each condition, the main disabling sequelae were identified and disability weights (DW) were derived based on short lay descriptions. Mortality (years of life lost (YLLs)) was estimated for RA and the rest category of 'other MSK', which includes a wide range of conditions such as systemic lupus erythematosus, other autoimmune diseases and osteomyelitis. A series of systematic reviews were conducted to determine the prevalence, incidence, remission, duration and mortality risk of each condition. A Bayesian meta-regression method was used to pool available data and to predict prevalence values for regions with no or scarce data. The DWs were applied to prevalence values for 1990, 2005 and 2010 to derive years lived with disability. These were added to YLLs to quantify overall burden (DALYs) for each condition. To estimate the burden of MSK disease arising from risk factors, population attributable fractions were determined for bone mineral density as a risk factor for fractures, the occupational risk of LBP and elevated body mass index as a risk factor for LBP and OA. Burden of Disease studies provide pivotal guidance for governments when determining health priority areas and allocating resources. Rigorous methods were used to derive the increasing global burden of MSK conditions.

The global burden of neck pain: estimates from the global burden of disease 2010 study.

OBJECTIVE: To estimate the global burden of neck pain. METHODS: Neck pain was defined as pain in the neck with or without pain referred into one or both upper limbs that lasts for at least 1 day. Systematic reviews were performed of the prevalence, incidence, remission, duration and mortality risk of neck pain. Four levels of severity were identified for neck pain with and without arm pain, each with their own disability weights. A Bayesian meta-regression method was used to pool prevalence and derive missing age/sex/region/year values. The disability weights were applied to prevalence values to derive the overall disability of neck pain expressed as years lived with disability (YLDs). YLDs have the same value as disability-adjusted life years as there is no evidence of mortality associated with neck pain. RESULTS: The global point prevalence of neck pain was 4.9% (95% CI 4.6 to 5.3). Disability-adjusted life years increased from 23.9 million (95% CI 16.5 to 33.1) in 1990 to 33.6 million (95% CI 23.5 to 46.5) in 2010. Out of all 291 conditions studied in the Global Burden of Disease 2010 Study, neck pain ranked 4th highest in terms of disability as measured by YLDs, and 21st in terms of overall burden. CONCLUSIONS: Neck pain is a common condition that causes substantial disability. With aging global populations, further research is urgently needed to better understand the predictors and clinical course of neck pain, as well as the ways in which neck pain can be prevented and better managed.

A glucose meter evaluation co-designed with both health professional and consumer input.

Health consumer's input into assessment of medical device safety is traditionally given either as part of study outcome (trial participants) or during post marketing surveillance. Direct consumer input into the methodological design of device assessment is less common. We discuss the difference in requirements for assessment of a measuring device from the consumer and clinician perspectives, using the example of hand held glucose meters. Around 80,000 New Zealanders with diabetes recently changed their glucose meter system, to enable ongoing access to PHARMAC subsidised meters and strips. Consumers were most interested in a direct comparison of their 'old' meter system (Accu-Chek Performa) with their 'new' meter system (CareSens brand, including the CareSens N POP), rather than comparisons against a laboratory standard. This direct comparison of meter/strip systems showed that the CareSens N POP meter read around 0.6 mmol/L higher than the Performa system. Whilst this difference is unlikely to result in major errors in clinical decision making such as major insulin dosing errors, this information is nevertheless of interest to consumers who switched meters so that they could maintain access to PHARMAC subsidised meters and strips. We recommend that when practical, the consumer perspective be incorporated into study design related to medical device assessment.

Gas phase controlled deposition of high quality large-area graphene films.

A gas phase controlled graphene synthesis resembling a CVD process that does not critically depend on cooling rates is reported. The controllable catalytic CVD permits high quality large-area graphene formation with deft control over the thickness from monolayers to thick graphitic structures at temperatures as low as 750 degrees C.

Myocardial subproteomic analysis of a constitutively active Rac1-expressing transgenic mouse with lethal myocardial hypertrophy.

A two-dimensional gel electrophoresis (2-DE)-based proteomic approach was used to study a transgenic mouse model of acerbated dilated cardiomyopathy in which the small monomeric GTPase, Rac1, was constitutively expressed exclusively in the myocardium. A subfractionation procedure allowed for the focused analysis of both cytoplasmic and myofilament protein-enriched extracts of ventricular tissue from Rac1 transgenic and age-matched nontransgenic (NTG) mice. The majority of these mice displayed severe hypertrophy (heart-to-body weight ratios >2-fold greater in the Rac1 mice) and died from overt heart failure between days 14 and 17. Comparative 2-DE analysis (pH 3-10, 12% SDS-PAGE) derived from Rac1 (n = 4) and NTG (n = 4) groups revealed differences in mean protein spot intensities. Twelve proteins from the cytoplasmic protein-enriched extract met our criteria for robustness and spot resolution and were identified. These proteins represent a broad distribution of cellular functions with only some previously implicated in myocardial hypertrophy. The myofilament subproteome displayed no change in posttranslational modification, but further analysis by one-dimensional Western blot showed increased quantities of myofilament proteins in the Rac1 mouse ventricles. Additionally, three proteins with different functionality that were altered in the cytoplasmic protein-enriched subproteome, tubulin beta-chain, manganese superoxide dismutase, and malate dehydrogenase, were analyzed at days 7, 9, and 11 to assess their role in the development of the dilated cardiomyopathic phenotype. The quantity of all three proteins peaked at day 9, suggesting an early response in cardiac hypertrophic failure.

Onset and manipulation of self-assembled morphology in freely standing polymer trilayer films.

We have used reflected light microscopy to study the lateral morphology which self-assembles at elevated temperatures in films consisting of a polyisoprene (PI) layer capped on both sides by polystyrene (PS) layers: freely standing PS/PI/PS trilayer films. Heating of the trilayer films causes the formation of a periodic, lateral morphology which is driven by the attractive dispersion interaction acting across the film. In our studies of the temperature dependence of the morphology, we find that the onset temperature for the formation of the morphology increases with increasing heating rate. By heating the films to temperatures greater than the glass transition temperature of the PS-capping layers, the morphology is removed. By heating and then cooling the films, the morphology formed upon heating disappears and reforms at right angles to the original morphology with a larger periodicity characteristic of the lower temperature. These results can be explained by considering the time and temperature dependence of Young's modulus of PS.

A new test set for validating predictions of protein-ligand interaction.

We present a large test set of protein-ligand complexes for the purpose of validating algorithms that rely on the prediction of protein-ligand interactions. The set consists of 305 complexes with protonation states assigned by manual inspection. The following checks have been carried out to identify unsuitable entries in this set: (1) assessing the involvement of crystallographically related protein units in ligand binding; (2) identification of bad clashes between protein side chains and ligand; and (3) assessment of structural errors, and/or inconsistency of ligand placement with crystal structure electron density. In addition, the set has been pruned to assure diversity in terms of protein-ligand structures, and subsets are supplied for different protein-structure resolution ranges. A classification of the set by protein type is available. As an illustration, validation results are shown for GOLD and SuperStar. GOLD is a program that performs flexible protein-ligand docking, and SuperStar is used for the prediction of favorable interaction sites in proteins. The new CCDC/Astex test set is freely available to the scientific community (http://www.ccdc.cam.ac.uk).

PRO_SELECT: combining structure-based drug design and array-based chemistry for rapid lead discovery. 2. The development of a series of highly potent and selective factor Xa inhibitors.

In silico screening of combinatorial libraries prior to synthesis promises to be a valuable aid to lead discovery. PRO_SELECT, a tool for the virtual screening of libraries for fit to a protein active site, has been used to find novel leads against the serine protease factor Xa. A small seed template was built upon using three iterations of library design, virtual screening, synthesis, and biological testing. Highly potent molecules with selectivity for factor Xa over other serine proteases were rapidly obtained.