Long-Term Programming of Antigen-Specific Immunity from Gene Expression Signatures in the PBMC of Rhesus Macaques Immunized with an SIV DNA Vaccine

While HIV-1-specific cellular immunity is thought to be critical for the suppression of viral replication, the correlates of protection have not yet been determined. Rhesus macaques (RM) are an important animal model for the study and development of vaccines against HIV/AIDS. Our laboratory has helped to develop and study DNA-based vaccines in which recent technological advances, including genetic optimization and in vivo electroporation (EP), have helped to dramatically boost their immunogenicity. In this study, RMs were immunized with a DNA vaccine including individual plasmids encoding SIV gag, env, and pol alone, or in combination with a molecular adjuvant, plasmid DNA expressing the chemokine ligand 5 (RANTES), followed by EP. Along with standard immunological assays, flow-based activation analysis without ex vivo restimulation and high-throughput gene expression analysis was performed. Strong cellular immunity was induced by vaccination which was supported by all assays including PBMC microarray analysis that identified the up-regulation of 563 gene sequences including those involved in interferon signaling. Furthermore, 699 gene sequences were differentially regulated in these groups at peak viremia following SIVmac251 challenge. We observed that the RANTES-adjuvanted animals were significantly better at suppressing viral replication during chronic infection and exhibited a distinct pattern of gene expression which included immune cell-trafficking and cell cycle genes. Furthermore, a greater percentage of vaccine-induced central memory CD8+ T-cells capable of an activated phenotype were detected in these animals as measured by activation analysis. Thus, co-immunization with the RANTES molecular adjuvant followed by EP led to the generation of cellular immunity that was transcriptionally distinct and had a greater protective efficacy than its DNA alone counterpart. Furthermore, activation analysis and high-throughput gene expression data may provide better insight into mechanisms of viral control than may be observed using standard immunological assays

Health reform and mortality in China : multilevel time-series analysis of regional and socioeconomic inequities in a sample of 73 million

This study was funded by the China National Science & Technology Pillar Program 2013 (2013BAI04B02) from the Ministry of Science and Technology. Funding was also received from the Australia China Science and Research Fund. Thomas Astell-Burt is supported by a National Heart Foundation of Australia Postdoctoral Fellowship (#100161).China's 2009 expansion of universal health insurance has received global interest, but little empirical investigation. This epidemiological study was a first attempt to assess potential impacts on population health and health equity. Multilevel negative binomial regression was used to analyse all-cause and non-communicable disease (NCD) mortality between 2006 and 2012 from a representative sample including all 31 provinces. The age-standardised ratios (per 100,000) in 2006 were 860.4 and 732.9 for mortality from all-causes and NCDs respectively. These ratios decreased over time to 737.5 (all-causes) and 642.9 (NCD) by 2012. Modelling indicated these trajectories were curvilinear, dipping more rapidly from 2009 onwards. Compared to the east, all-cause mortality was higher in other regions (e.g. northwest RR: 1.34, 95% CI: 1.20, 1.48). Compared to more affluent urban areas, rate ratios for all-cause mortality were 1.23 (95% CI: 0.97, 1.54) in the least affluent urban areas, 1.22 (95% CI: 1.02, 1.46) in affluent rural areas and 1.64 (95% CI: 1.51, 1.79) in the least affluent rural areas. These health inequities were largely repeated for NCD mortality and did not vary spatiotemporally. Overall, universal health insurance in China may have accelerated reductions in all-cause and NCD mortality, but potential impacts on health inequity may take longer to manifest.Publisher PDFPeer reviewe

Analysis of health service amenable and non-amenable mortality before and since China\u27s expansion of health coverage in 2009

Objective To explore early impacts of China\u27s health reforms in 2009 on mortality. Methods Annual mortality counts were obtained from 161 counties across all 31 provinces of mainland China between 2006 and 2012. We examined time-series of health service amenable mortality counts, including separate analyses for deaths from stroke and ischaemic heart diseases (IHD). Non-amenable mortality counts, including separate models for oesophageal and pancreatic cancers, were also analysed as part of a negative-outcome strategy to provide stronger foundations for falsification. Deaths due to amenable causes were hypothesised to decrease, whereas non-amenable causes of mortality would remain uninfluenced. All analyses were conducted using multilevel negative binomial regression. Results Geographical variation was observed for each mortality indicator, especially for IHD, oesophageal and pancreatic cancers. Negative covariances in all models indicated slight degrees of convergence in these geographic variations over time (but not significantly for deaths from oesophageal and pancreatic cancers). Linear and square functions of time indicated a curvilinear inverted parabolic trend between 2006 and 2012 for stroke and IHD mortality. Reduction in health-service amenable mortality over time was observed, but also for health service non-amenable mortality, including deaths from oesophageal cancer. Pancreatic cancer was found to increase across the study period. In counties where residents had more years of education, mortality from stroke was lower and reducing faster over time. A similar spatiotemporal patterning was observed for deaths from oesophageal cancer, and health service amenable and non-amenable causes. Counties with higher mean education years had higher mortality from IHD and pancreatic cancer, but also larger reductions in mortality were evident in areas with greater years of education. Conclusions Although there was no clear evidence of an early impact of China\u27s health reform on mortality, this does not rule out potentially important contributions to reducing the burden of disease in the longer term

Years of life lost and life expectancy attributable to ambient temperature: A time series study in 93 Chinese cities

Abstract Although increasing evidence has reported that unfavorable temperature may lead to increased premature mortality, a systematic assessment is lacking on the impact of ambient temperature on years of life lost (YLL) and life expectancy in China. Daily data on mortality, YLL, meteorological factors and air pollution were obtained from 93 Chinese cities during 2013–2016. A two-stage analytic approach was applied for statistical analysis. At the first stage, a distributed lag non-linear model with a Gaussian link was used to estimate the city-specific association between ambient temperature and YLLs. At the second stage, a meta-analysis was used to obtain the effect estimates at regional and national levels. We further estimated the corresponding YLLs and average life expectancy loss per deceased person attributable to the non-optimum temperature exposures based on the established associations. We observed ‘U’ or ‘J’ shaped associations between daily temperature and YLL. The heat effect appeared on the current day and lasted for only a few days, while the cold effect appeared a few days later and lasted for longer. In general, 6.90% (95% confidence interval (CI): 4.62%, 9.18%) of YLLs could be attributed to non-optimum temperatures at the national level, with differences across different regions, ranging from 5.36% (95% CI: −3.36%, 6.89%) in east region to 9.09% (95% CI: −5.55%, 23.73%) in northwest region. For each deceased person, we estimated that non-optimum temperature could cause a national-averaged 1.02 years (95% CI: 0.68, 1.36) of life loss, with a significantly higher effect due to cold exposure (0.89, 95% CI: 0.59, 1.19) than that of hot exposure (0.13, 95% CI: 0.09, 0.16). This national study provides evidence that both cold and hot weather might result in significant YLL and lower life expectancy. Regional adaptive policies and interventions should be considered to reduce the mortality burden associated with the non-optimum temperature exposures

Health reform and mortality in China:multilevel time-series analysis of regional and socioeconomic inequities in a sample of 73 million

China's 2009 expansion of universal health insurance has received global interest, but little empirical investigation. This epidemiological study was a first attempt to assess potential impacts on population health and health equity. Multilevel negative binomial regression was used to analyse all-cause and non-communicable disease (NCD) mortality between 2006 and 2012 from a representative sample including all 31 provinces. The age-standardised ratios (per 100,000) in 2006 were 860.4 and 732.9 for mortality from all-causes and NCDs respectively. These ratios decreased over time to 737.5 (all-causes) and 642.9 (NCD) by 2012. Modelling indicated these trajectories were curvilinear, dipping more rapidly from 2009 onwards. Compared to the east, all-cause mortality was higher in other regions (e.g. northwest RR: 1.34, 95% CI: 1.20, 1.48). Compared to more affluent urban areas, rate ratios for all-cause mortality were 1.23 (95% CI: 0.97, 1.54) in the least affluent urban areas, 1.22 (95% CI: 1.02, 1.46) in affluent rural areas and 1.64 (95% CI: 1.51, 1.79) in the least affluent rural areas. These health inequities were largely repeated for NCD mortality and did not vary spatiotemporally. Overall, universal health insurance in China may have accelerated reductions in all-cause and NCD mortality, but potential impacts on health inequity may take longer to manifest.</p

Spatiotemporal variations in lung cancer mortality in China between 2006 and 2012 : a multilevel analysis

We investigated temporal trends and geographical variations in lung cancer mortality in China from 2006 to 2012. Lung cancer mortality counts for people aged over 40 years were extracted from the China Mortality Surveillance System for 161 disease surveillance points. Negative binomial regression was used to investigate potential spatiotemporal variation and correlations with age, gender, urbanization, and region. Lung cancer mortality increased in China over the study period from 78.77 to 85.63 (1/100,000), with higher mortality rates evident in men compared to women. Median rate ratios (MRRs) indicated important geographical variation in lung cancer mortality between provinces (MRR = 1.622) and counties/districts (MRR = 1.447). On average, lung cancer mortality increased over time and was positively associated with county-level urbanization (relative risk (RR) = 1.15). Lung cancer mortality seemed to decrease in urban and increase in rural areas. Compared to the northwest, mortality was higher in the north (RR = 1.98), east (RR = 1.87), central (RR = 1.87), and northeast (RR = 2.44). Regional differences and county-level urbanization accounted for 49.4% and 8.7% of provincial and county variation, respectively. Reductions in lung cancer mortality in urban areas may reflect improvements in access to preventive healthcare and treatment services. Rising mortality in rural areas may reflect a clustering of risk factors associated with rapid urbanization

Temporal trends and geographic variations in dementia mortality in China between 2006 and 2012 : multilevel evidence from a nationally representative sample

Objectives: We aimed to explore the temporal trends and geographic variations in dementia mortality in China. Materials and Methods: Annual dementia mortality counts (years 2006 to 2012) in 161 counties and districts (Disease Surveillance Points, DSP) were extracted from the nationally representative China Mortality Surveillance System and stratified by 5-year age group (aged >65), sex, and time. These counts were linked to annually adjusted denominator populations. Multilevel negative binomial regression with random intercepts and slopes were used to investigate spatiotemporal variation in dementia mortality. Results: Dementia mortality varied over 2-fold between DSPs (median rate ratio: 2.59). Significant variation in DSP slopes through time (variance 0.075, SE 0.020) indicated spatiotemporal variations. Mortality rates were significantly higher in the east (rate ratio 2.28; 95% confidence intervals, 1.45-3.60) compared with the north. There was a declining trend in 2 (east and northwest) of the 7 regions. Dementia mortality decreased by 15% in urban areas but increased by 24% in rural areas. Conclusions: Our findings indicate that regional inequalities in dementia mortality are salient, and the increase in mortality rates in rural areas is an emerging public health challenge in China. Tailored preventive health strategies should be in place to narrow down this avoidable and wholly unnecessary inequality

Analysis of health service amenable and non-amenable mortality before and since China’s expansion of health coverage in 2009

Objective: To explore early impacts of China’s health reforms in 2009 on mortality. Methods: Annual mortality counts were obtained from 161 counties across all 31 provinces of mainland China between 2006 and 2012. We examined time series of health service amenable mortality counts, including separate analyses for deaths from stroke and ischaemic heart diseases (IHD). Non-amenable mortality counts, including separate models for oesophageal and pancreatic cancers, were also analysed as part of a negative-outcome strategy to provide stronger foundations for falsification. Deaths due to amenable causes were hypothesised to decrease, whereas non-amenable causes of mortality would remain uninfluenced. All analyses were conducted using multilevel negative binomial regression. Results: Geographical variation was observed for each mortality indicator, especially for IHD, oesophageal and pancreatic cancers. Negative covariances in all models indicated slight degrees of convergence in these geographic variations over time (but not significantly for deaths from oesophageal and pancreatic cancers). Linear and square functions of time indicated a curvilinear inverted parabolic trend between 2006 and 2012 for stroke and IHD mortality. Reduction in health service amenable mortality over time was observed, but also for health service non-amenable mortality, including deaths from oesophageal cancer. Pancreatic cancer was found to increase across the study period. In counties where residents had more years of education, mortality from stroke was lower and reducing faster over time. A similar spatiotemporal patterning was observed for deaths from oesophageal cancer, and health service amenable and non-amenable causes. Counties with higher mean education years had higher mortality from IHD and pancreatic cancer, but also larger reductions in mortality were evident in areas with greater years of education. Conclusions: Although there was no clear evidence of an early impact of China’s health reform on mortality, this does not rule out potentially important contributions to reducing the burden of disease in the longer term