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Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.

The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.

The liver is a major metastatic site (organ) for gastrointestinal cancers (such as colorectal, gastric, and pancreatic cancers) as well as non-gastrointestinal cancers (such as lung, breast, and melanoma cancers). Due to the innate anatomical position of the liver, the apoptosis of T cells in the liver, the unique metabolic regulation of hepatocytes and other potential mechanisms, the liver tends to form an immunosuppressive microenvironment and subsequently form a pre-metastatic niche (PMN), which can promote metastasis and colonization by various tumor cells(TCs). As a result, the critical role of immunoresponse in liver based metastasis has become increasingly appreciated. T cells, a centrally important member of adaptive immune response, play a significant role in liver based metastases and clarifying the different roles of the various T cells subsets is important to guide future clinical treatment. In this review, we first introduce the predisposing factors and related mechanisms of liver metastasis (LM) before introducing the PMN and its transition to LM. Finally, we detail the role of different subsets of T cells in LM and advances in the management of LM in order to identify potential therapeutic targets for patients with LM.

Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.

The ability of the human liver to both synthesize extracellular matrix(ECM), as well as regulate fibrogenesis, are integral functions to maintaining homoeostasis. Chronic liver injury stimulates fibrogenesis in response to the imbalance between ECM accumulation and fibrosis resolution. Liver disease that induces fibrogenesis is associated with multiple risk factors like hepatitis infection, schistosomiasis, alcohol, certain drugs, toxicants and emerging aetiology like diabetes and obesity. The activation of hepatic stellate cells (HSCs), whose function is to generate and accumulate ECM, is a pivotal event in liver fibrosis. Simultaneously, HSCs selectively promote regulatory T-cells (Tregs) in an interleukin-2–dependent pattern that displays a dual relationship. On the one hand, Tregs can protect HSCs from NK cell attack, while on the other hand, they demonstrate an inhibitory effect on HSCs. This paper reviews the dual role of Tregs in liver fibrogenesis which includes its promotion of immunosuppression, as well as its activation of fibrosis. In particular, the balance between Tregs and the Th17 cell population, which produce interleukin (IL)-17 and IL-22, is explored to demonstrate their key role in maintaining homoeostasis and immunoregulation. The contradictory roles of Tregs in liver fibrosis in different immune microenvironments and molecular pathways need to be better understood if they are to be deployed to manage this disease.

Background Infant mortality rate (IMR) is regarded as an important indicator of population health. IMR rates vary substantially with the highest found in sub-Saharan Africa (SSA) compared to the lowest in Europe. Identifying spatial disparities in IMR and quantifying attributable risk factors is essential for policymakers when tailoring time-appropriate interventions at a global, regional, and country level. Methods Data for 192 countries were extracted from the World Bank Development Indicator database for the period 1990–2011. Spatial clustering was used to identify significant higher-risk IMR countries. A robust ecological generalized linear negative binomial regression model was used to quantify risk factors and associated decomposition values (Shapley). Results Significant reductions were observed in IMR for all of the World Health Organization regions for the period 1990–2011 except for SSA, which indicated a reversal of this trend in the 1990s due to HIV. Significant high-risk clustering of IMR is also indicated in SSA countries and parts of Asia. Maternal mortality (survival), lack of water and sanitation and female education were confirmed as prominent and high attributable risk factors for IMR. Distinct temporal changes in the attributability of these factors were observed, as well as significant heterogeneity with regards to the most attributable factor by region and country. Conclusions Our study suggests that maternal mortality is the most prominent attributable risk factor for infant mortality, followed by lack of access to sanitation, lack of access to water, and lower female education. Variation exists across regions and countries with regards to the most attributable factor. Our study also suggests significant underestimation of IMR in regions known for poorer data quality. The results will aid policymakers in re-tailoring time-appropriate interventions to more effectively reduce IMR in line with Millennium Development Goal 4.

ObjectivesTo assess space-time trends in malnutrition and associated risk factors among children (<5 years) in South Africa.DesignMultiround national panel survey using multistage random sampling.SettingNational, community based.ParticipantsCommunity-based sample of children and adults. Sample size: 3254 children in wave 1 (2008) to 4710 children in wave 5 (2017).Primary outcomesStunting, wasting/thinness and obesity among children (<5). Classification was based on anthropometric (height and weight) z-scores using WHO growth standards.ResultsBetween 2008 and 2017, a larger decline nationally in stunting among children (<5) was observed from 11.0% to 7.6% (p=0.007), compared with thinness/wasting (5.2% to 3.8%, p=0.131) and obesity (14.5% to 12.9%, p=0.312). A geographic nutritional gradient was observed with obesity more pronounced in the east of the country and thinness/wasting more pronounced in the west. Approximately 73% of districts had an estimated wasting prevalence below the 2025 target threshold of 5% in 2017 while 83% and 88% of districts achieved the necessary relative reduction in stunting and no increase in obesity respectively from 2012 to 2017 in line with 2025 targets. African ethnicity, male gender, low birth weight, lower socioeconomic and maternal/paternal education status and rural residence were significantly associated with stunting. Children in lower income and food-insecure households with young malnourished mothers were significantly more likely to be thin/wasted while African children, with higher birth weights, living in lower income households in KwaZulu-Natal and Eastern Cape were significantly more likely to be obese.ConclusionsWhile improvements in stunting have been observed, thinness/wasting and obesity prevalence remain largely unchanged. The geographic and sociodemographic heterogeneity in childhood malnutrition has implications for equitable attainment of global nutritional targets for 2025, with many districts having dual epidemics of undernutrition and overnutrition. Effective subnational-level public health planning and tailored interventions are required to address this challenge.

Health inequities in developing countries are difficult to eradicate because of limited resources. The neglect of adult mortality in Sub-Saharan Africa (SSA) is a particular concern. Advances in data availability, software and analytic methods have created opportunities to address this challenge and tailor interventions to small areas. This study demonstrates how a generic framework can be applied to guide policy interventions to reduce adult mortality in high risk areas. The framework, therefore, incorporates the spatial clustering of adult mortality, estimates the impact of a range of determinants and quantifies the impact of their removal to ensure optimal returns on scarce resources. Data from a national cross-sectional survey in 2007 were used to illustrate the use of the generic framework for SSA and elsewhere. Adult mortality proportions were analyzed at four administrative levels and spatial analyses were used to identify areas with significant excess mortality. An ecological approach was then used to assess the relationship between mortality \"hotspots\" and various determinants. Population attributable fractions were calculated to quantify the reduction in mortality as a result of targeted removal of high-impact determinants. Overall adult mortality rate was 145 per 10,000. Spatial disaggregation identified a highly non-random pattern and 67 significant high risk local municipalities were identified. The most prominent determinants of adult mortality included HIV antenatal sero-prevalence, low SES and lack of formal marital union status. The removal of the most attributable factors, based on local area prevalence, suggest that overall adult mortality could be potentially reduced by ∼90 deaths per 10,000. The innovative use of secondary data and advanced epidemiological techniques can be combined in a generic framework to identify and map mortality to the lowest administration level. The identification of high risk mortality determinants allows health authorities to tailor interventions at local level. This approach can be replicated elsewhere.

Lung cancer incidence is increasing in many low-to-middle-income countries and is significantly under-reported in Africa, which could potentially mislead policy makers when prioritising disease burden. We employed an ecological correlation study design using countrylevel lung cancer incidence data and associated determinant data. Lagged prevalence of smoking and other exposure data were used to account for exposure-disease latency. A multivariable Poisson model was employed to estimate missed lung cancer in countries lacking incidence data. Projections were further refined to remove potential deaths from infectious/external competing causes. Global lung cancer incidence was much lower among females vs males (13.6 vs 34.2 per 100,000). Distinct spatial heterogeneity was observed for incident lung cancer and appeared concentrated in contiguous regions. Our model predicted a revised global lung cancer incidence in 2012 of 23.6 compared to the Globocan 2012 estimate of 23.1, amounting to ~38,101 missed cases (95% confidence interval: 28,489-47,713). The largest relative under-estimation was predicted for Africa, Central America and the Indian Ocean regions (Comoros, Madagascar, Mauritius, Mayotte, Reunion, Seychelles). Our results suggest substantial underreporting of lung cancer incidence, specifically in developing countries (e.g. Africa). The missed cost of treating these cases could amount to >US$ 130 million based on recent developing setting costs for treating earlier stage lung cancer. The full cost is not only under-estimated, but also requires substantial additional social/family inputs as evidenced in more developed settings like the European Union. This represents a major public health problem in developing settings (e.g. Africa) with limited healthcare resources.

Background: The ability of the Baltic Dry Index to predict economic activity has been evaluated in a number of developed and developing countries. Aim: Firstly, the article determines the primary factors driving the dynamics of the Baltic Dry Index (BDI) and, secondly, whether the BDI can predict future share price reactions on the Johannesburg Stock Exchange All Share Index (JSE ALSI), South Africa. Setting: This article investigates the dynamics and predictive properties of the BDI in South Africa between 1985 and 2016. Methods: The article uses a review of a wide range of published data and two time-series data sets to adopt a mixed methods approach. An inductive contents analysis is used to answer the first research question and a combination of a unit root test, correlation analysis and a Granger causality model is employed to test the second research question. Results: The results show that the BDI price is primarily driven by four underlying constructs that include the supply and demand for dry bulk shipping, as well as risk, cost and logistics management factors. Secondly, the results indicate a break in the BDI data set in July 2008 that influences a fundamental change in its relationship with the JSE ALSI index. In the pre-break period (1985 to 2008), the BDI is positively correlated with the ALSI (0.837, α = 0.05) before sharply diverging in the second period from August 2008 to 2016. In the first period, the BDI showed an optimal lag period of 6 months as a predictor of the ALSI index, but this predictive ability ceases after July 2008. The article makes a two-part contribution. Firstly, it demonstrates that the BDI is a useful predictor of future economic activity in an African developing country. Secondly, the BDI can be incorporated in government and industry sector planning models as a variable to assess future gross domestic product trends. Conclusion: The study confirms that the BDI is only a reliable indicator of future economic activity when the supply of shipping capacity is well matched with the demand.