A quantitative UHPLC-MS/MS method for the growth hormone-releasing peptide-6 determination in complex biological matrices and transdermal formulations.

Growth hormone-releasing peptide-6 (GHRP-6) is part of a group of small synthetic peptides with potent GH-releasing activity that have gained attention in the last two decades by virtue of their cyto- and cardioprotective effects. Despite numerous preclinical studies highlighting the potential cardiovascular benefits of GHRP-6, confirmation of clinical efficacy is still awaited. Recent advances in transdermal drug delivery systems have been made to address challenges related to the poor skin permeation rate of peptides by using pain-free microneedle (MN) devices. Accordingly, highly sensitive and validated analytical methods are required for the potential clinical translation of MN-based peptides. The ultra-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) methods developed in this study aimed to quantify GHRP-6 in biological matrices (plasma, skin) and dissolving polymeric MNs. UHPLC/MS-MS method detection limits of 0.1, 1.1, 0.9 and 1.5 ng/mL were achieved in neat solution, plasma, MN polymer solution, and skin matrices, respectively. Method validation also involved assessment of precision, accuracy, limits of quantification, linearity of matched calibration curves (R2 > 0.990), extraction recovery, matrix effect, stability studies, selectivity, and carry-over effect. Additionally, quality control samples were analyzed at three concentration levels to determine recovery (85-109%) and accuracy/bias (3.2-14.7%). Intra- and inter-day precision were within the range of acceptance (RSDs of 3.0-13.9% and 0.4-14.5%, respectively). The validity and applicability of such methods were successfully demonstrated for transdermal GHRP-6 delivery using GHRP-6-loaded MN patches applied to pig skin.

Transformation of the education of health professionals in China: progress and challenges.

In this Review we examine the progress and challenges of China's ambitious 1998 reform of the world's largest health professional educational system. The reforms merged training institutions into universities and greatly expanded enrolment of health professionals. Positive achievements include an increase in the number of graduates to address human resources shortages, acceleration of production of diploma nurses to correct skill-mix imbalance, and priority for general practitioner training, especially of rural primary care workers. These developments have been accompanied by concerns: rapid expansion of the number of students without commensurate faculty strengthening, worries about dilution effect on quality, outdated curricular content, and ethical professionalism challenged by narrow technical training and growing admissions of students who did not express medicine as their first career choice. In this Review we underscore the importance of rebalance of the roles of health sciences institutions and government in educational policies and implementation. The imperative for reform is shown by a looming crisis of violence against health workers hypothesised as a result of many factors including deficient educational preparation and harmful profit-driven clinical practices.

The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions.

The Global Burden of Disease (GBD) Study 2010 estimated the GBD attributable to 15 categories of skin disease from 1990 to 2010 for 187 countries. For each of the following diseases, we performed systematic literature reviews and analyzed resulting data: eczema, psoriasis, acne vulgaris, pruritus, alopecia areata, decubitus ulcer, urticaria, scabies, fungal skin diseases, impetigo, abscess, and other bacterial skin diseases, cellulitis, viral warts, molluscum contagiosum, and non-melanoma skin cancer. We used disability estimates to determine nonfatal burden. Three skin conditions, fungal skin diseases, other skin and subcutaneous diseases, and acne were in the top 10 most prevalent diseases worldwide in 2010, and eight fell into the top 50; these additional five skin problems were pruritus, eczema, impetigo, scabies, and molluscum contagiosum. Collectively, skin conditions ranged from the 2nd to 11th leading cause of years lived with disability at the country level. At the global level, skin conditions were the fourth leading cause of nonfatal disease burden. Using more data than has been used previously, the burden due to these diseases is enormous in both high- and low-income countries. These results argue strongly to include skin disease prevention and treatment in future global health strategies as a matter of urgency.

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.

Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.

BACKGROUND: Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time. METHODS: We calculated DALYs as the sum of years of life lost (YLLs) and years lived with disability (YLDs). DALYs were calculated for 291 causes, 20 age groups, both sexes, and for 187 countries, and aggregated to regional and global estimates of disease burden for three points in time with strictly comparable definitions and methods. YLLs were calculated from age-sex-country-time-specific estimates of mortality by cause, with death by standardised lost life expectancy at each age. YLDs were calculated as prevalence of 1160 disabling sequelae, by age, sex, and cause, and weighted by new disability weights for each health state. Neither YLLs nor YLDs were age-weighted or discounted. Uncertainty around cause-specific DALYs was calculated incorporating uncertainty in levels of all-cause mortality, cause-specific mortality, prevalence, and disability weights. FINDINGS: Global DALYs remained stable from 1990 (2·503 billion) to 2010 (2·490 billion). Crude DALYs per 1000 decreased by 23% (472 per 1000 to 361 per 1000). An important shift has occurred in DALY composition with the contribution of deaths and disability among children (younger than 5 years of age) declining from 41% of global DALYs in 1990 to 25% in 2010. YLLs typically account for about half of disease burden in more developed regions (high-income Asia Pacific, western Europe, high-income North America, and Australasia), rising to over 80% of DALYs in sub-Saharan Africa. In 1990, 47% of DALYs worldwide were from communicable, maternal, neonatal, and nutritional disorders, 43% from non-communicable diseases, and 10% from injuries. By 2010, this had shifted to 35%, 54%, and 11%, respectively. Ischaemic heart disease was the leading cause of DALYs worldwide in 2010 (up from fourth rank in 1990, increasing by 29%), followed by lower respiratory infections (top rank in 1990; 44% decline in DALYs), stroke (fifth in 1990; 19% increase), diarrhoeal diseases (second in 1990; 51% decrease), and HIV/AIDS (33rd in 1990; 351% increase). Major depressive disorder increased from 15th to 11th rank (37% increase) and road injury from 12th to 10th rank (34% increase). Substantial heterogeneity exists in rankings of leading causes of disease burden among regions. INTERPRETATION: Global disease burden has continued to shift away from communicable to non-communicable diseases and from premature death to years lived with disability. In sub-Saharan Africa, however, many communicable, maternal, neonatal, and nutritional disorders remain the dominant causes of disease burden. The rising burden from mental and behavioural disorders, musculoskeletal disorders, and diabetes will impose new challenges on health systems. Regional heterogeneity highlights the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account. Because of improved definitions, methods, and data, these results for 1990 and 2010 supersede all previously published Global Burden of Disease results. FUNDING: Bill & Melinda Gates Foundation.

The global health system: actors, norms, and expectations in transition.

In the first in a series of four articles highlighting the changing nature of global health institutions, Nicole Szlezák and colleagues outline the origin and aim of the series.

Financing of global health: tracking development assistance for health from 1990 to 2007.

BACKGROUND: The need for timely and reliable information about global health resource flows to low-income and middle-income countries is widely recognised. We aimed to provide a comprehensive assessment of development assistance for health (DAH) from 1990 to 2007. METHODS: We defined DAH as all flows for health from public and private institutions whose primary purpose is to provide development assistance to low-income and middle-income countries. We used several data sources to measure the yearly volume of DAH in 2007 US$, and created an integrated project database to examine the composition of this assistance by recipient country. FINDINGS: DAH grew from $5.6 billion in 1990 to $21.8 billion in 2007. The proportion of DAH channelled via UN agencies and development banks decreased from 1990 to 2007, whereas the Global Fund to Fight AIDS, Tuberculosis and Malaria, the Global Alliance for Vaccines and Immunization (GAVI), and non-governmental organisations became the conduit for an increasing share of DAH. DAH has risen sharply since 2002 because of increases in public funding, especially from the USA, and on the private side, from increased philanthropic donations and in-kind contributions from corporate donors. Of the $13.8 [corrected] billion DAH in 2007 for which project-level information was available, $4.9 [corrected] billion was for HIV/AIDS, compared with $0.6 [corrected] billion for tuberculosis, $0.7 [corrected] billion for malaria, and $0.9 billion for health-sector support. Total DAH received by low-income and middle-income countries was positively correlated with burden of disease, whereas per head DAH was negatively correlated with per head gross domestic product. INTERPRETATION: This study documents the substantial rise of resources for global health in recent years. Although the rise in DAH has resulted in increased funds for HIV/AIDS, other areas of global health have also expanded. The influx of funds has been accompanied by major changes in the institutional landscape of global health, with global health initiatives such as the Global Fund and GAVI having a central role in mobilising and channelling global health funds. FUNDING: Bill & Melinda Gates Foundation.

The burden of disease and injury in the United States 1996.

BACKGROUND: Burden of disease studies have been implemented in many countries using the Disability-Adjusted Life Year (DALY) to assess major health problems. Important objectives of the study were to quantify intra-country differentials in health outcomes and to place the United States situation in the international context. METHODS: We applied methods developed for the Global Burden of Disease (GBD) to data specific to the United States to compute Disability-Adjusted Life Years. Estimates are provided by age and gender for the general population of the United States and for each of the four official race groups: White; Black; American Indian or Alaskan Native; and Asian or Pacific Islander. Several adjustments of GBD methods were made: the inclusion of race; a revised list of causes; and a revised algorithm to allocate cardiovascular disease garbage codes to ischaemic heart disease. We compared the results of this analysis to international estimates published by the World Health Organization for developed and developing regions of the world. RESULTS: In the mid-1990s the leading sources of premature death and disability in the United States, as measured by DALYs, were: cardiovascular conditions, breast and lung cancers, depression, osteoarthritis, diabetes mellitus, and alcohol use and abuse. In addition, motor vehicle-related injuries and the HIV epidemic exacted a substantial toll on the health status of the US population, particularly among racial minorities. The major sources of death and disability in these latter populations were more similar to patterns of burden in developing rather than developed countries. CONCLUSION: Estimating DALYs specifically for the United States provides a comprehensive assessment of health problems for this country compared to what is available using mortality data alone.

Eight Americas: investigating mortality disparities across races, counties, and race-counties in the United States.

BACKGROUND: The gap between the highest and lowest life expectancies for race-county combinations in the United States is over 35 y. We divided the race-county combinations of the US population into eight distinct groups, referred to as the "eight Americas," to explore the causes of the disparities that can inform specific public health intervention policies and programs. METHODS AND FINDINGS: The eight Americas were defined based on race, location of the county of residence, population density, race-specific county-level per capita income, and cumulative homicide rate. Data sources for population and mortality figures were the Bureau of the Census and the National Center for Health Statistics. We estimated life expectancy, the risk of mortality from specific diseases, health insurance, and health-care utilization for the eight Americas. The life expectancy gap between the 3.4 million high-risk urban black males and the 5.6 million Asian females was 20.7 y in 2001. Within the sexes, the life expectancy gap between the best-off and the worst-off groups was 15.4 y for males (Asians versus high-risk urban blacks) and 12.8 y for females (Asians versus low-income southern rural blacks). Mortality disparities among the eight Americas were largest for young (15-44 y) and middle-aged (45-59 y) adults, especially for men. The disparities were caused primarily by a number of chronic diseases and injuries with well-established risk factors. Between 1982 and 2001, the ordering of life expectancy among the eight Americas and the absolute difference between the advantaged and disadvantaged groups remained largely unchanged. Self-reported health plan coverage was lowest for western Native Americans and low-income southern rural blacks. Crude self-reported health-care utilization, however, was slightly higher for the more disadvantaged populations. CONCLUSIONS: Disparities in mortality across the eight Americas, each consisting of millions or tens of millions of Americans, are enormous by all international standards. The observed disparities in life expectancy cannot be explained by race, income, or basic health-care access and utilization alone. Because policies aimed at reducing fundamental socioeconomic inequalities are currently practically absent in the US, health disparities will have to be at least partly addressed through public health strategies that reduce risk factors for chronic diseases and injuries.

Effect of the Global Alliance for Vaccines and Immunisation on diphtheria, tetanus, and pertussis vaccine coverage: an independent assessment.

BACKGROUND: The Global Alliance for Vaccines and Immunisation (GAVI) was created in 1999 to enable even the poorest countries to provide vaccines to all children. We aimed to assess the effect of GAVI on combined diphtheria, tetanus, and pertussis vaccine (DTP3) coverage. METHODS: We examined the relation between DTP3 coverage for GAVI recipient countries from 1995 to 2004 and immunisation services support (ISS) and non-ISS expenditure per surviving child, controlling for income per head and local political governance variables. We analysed DTP3 coverage reported by governments and estimated by WHO/UNICEF. We also investigated the effect of GAVI on country reporting behaviour. RESULTS: In countries with DTP3 coverage of 65% or less at baseline, ISS spending per surviving child had a significant positive effect on DTP3 coverage (p=0.0005). This effect was not present in countries with DTP3 coverage of 65-80% or 80% or more at baseline. If ISS expenditure only is assessed, the estimated cost per additional child immunised in countries with baseline coverage of 65% or less is US$14 and if ISS and non-ISS expenditures are included the cost per child is almost $20. INTERPRETATION: The success of ISS funding in countries with baseline DTP3 coverage of 65% or less provides evidence that a public-private partnership can work to reverse a negative trend in global health and that performance-related disbursement can work in some settings. Because ISS funding seems to have no effect in countries with baseline coverage greater than 65%, GAVI should consider redistributing its resources to countries with the lowest coverage.

Absorptive capacity and disbursements by the Global Fund to Fight AIDS, Tuberculosis and Malaria: analysis of grant implementation.

BACKGROUND: The Global Fund to Fight AIDS, Tuberculosis and Malaria was launched in 2002 to attract and rapidly disburse money to fight these diseases. However, some commentators believe that poor countries cannot effectively use such resources to increase delivery of their health programmes-referred to as a lack of absorptive capacity. We aimed to investigate the major determinants of grant implementation in developing countries. METHODS: With information available publicly on the Global Fund's website, we did random-effects analysis to investigate the effect of grant characteristics, types of primary recipient and local fund agent, and country attributes on disbursements that were made between 2003 and 2005 (phase one of Global Fund payments). To check the robustness of findings, regression results from alternative estimation methods and model specifications were also tested. FINDINGS: Grant characteristics--such as size of commitment, lag time between signature and first disbursement, and funding round-had significant effects on grant implementation. Enhanced political stability was associated with high use of grants. Low-income countries, and those with less-developed health systems for a given level of income, were more likely to have a higher rate of grant implementation than nations with higher incomes or more-developed health systems. INTERPRETATION: The higher rate of grant implementation seen in countries with low income and low health-spending lends support to proponents of major increases in health assistance for the poorest countries and argues that focusing resources on low-income nations, particularly those with political stability, will not create difficulties of absorptive capacity. Our analysis was restricted to grant implementation, which is one part of the issue of absorptive capacity. In the future, assessment of the effect of Global Fund grants on intervention coverage will be vital.

Assessing the burden of disease in the United States using disability-adjusted life years.

OBJECTIVES: Burden of disease studies have been implemented in many countries using the disability-adjusted life year (DALY) to assess major health problems. METHODS: We applied methods developed by the World Bank and World Health Organization (WHO) to data specific to the United States to compute DALYs. We compared the results of this analysis to international estimates published by WHO for developed and developing regions of the world. RESULTS: In the mid-1990s, the leading sources of premature death and disability in the United States, as measured by DALYs, were cardiovascular conditions, breast and lung cancers, depression, osteoarthritis, diabetes mellitus, and alcohol use and abuse. In addition, motor vehicle-related injuries and the HIV epidemic exacted a substantial toll on the health status of the U.S. population, particularly among racial/ethnic minorities. The major sources of death and disability in these latter populations were more similar to patterns of burden in developing rather than developed countries. CONCLUSIONS: This analysis provides the first detailed, comprehensive estimates using DALYs of the fatal and nonfatal conditions that exact large health burdens in the United States.