Comparing regional organizations in global multilateral institutions:ASEAN, the EU and the UN

Structural change brought about by the end of the Cold War and accelerated globalisation have transformed the global environment. A global governance complex is emerging, characterised by an ever-greater functional and regulatory role for multilateral organisations such as the United Nations (UN) and its associated agencies. The evolving global governance framework has created opportunities for regional organisations to participate as actors within the UN (and other multilateral institutions). This article compares the European Union (EU) and Association of Southeast Asian Nations (ASEAN) as actors within the UN network. It begins by extrapolating framework conditions for the emergence of EU and ASEAN actorness from the literature. The core argument of this article is that EU and ASEAN actorness is evolving in two succinct stages: Changes in the global environment create opportunities for the participation of regional organisations in global governance institutions, exposing representation and cohesion problems at the regional level. In response, ASEAN and the EU have initiated processes of institutional adaptation

Molecular epidemiology of Hepatitis B virus genotypes in Pakistan

<p>Abstract</p> <p>Background</p> <p>Eight genotypes of Hepatitis B virus designated A-H, have been known but in Pakistan, no such data is available on the prevalent HBV genotypes. Therefore, the subject study was conducted to determine HBV genotypes in the indigenous Pakistani population.</p> <p>Methods</p> <p>A total of 690 individuals were enrolled for HBV screening with EIA and nested PCR. Positive samples were further analyzed to determine HBV genotypes (A-F) by multiplex-PCR using type specific primers.</p> <p>Results</p> <p>110 (15.94%) individuals were positive for HBV, including 64% males and 36% females. Out of these, 66 samples (65.34%) were classified into genotype D, 27 (26.73%) were of genotype B while 5(4.95%) had genotype A. In 3 (2.98%) samples, multiple genotypes were detected (genotype A+B; 2(1.99%) and genotypes B+D; 1(0.99%). Nine (8.18%) samples remained untyable.</p> <p>Conclusion</p> <p>In Asia, genotypes B and C are the most prevalent but our study reveals that genotype D is predominant and HBV infection constitutes a significant health problem in Pakistan.</p

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Considering Trauma Exposure in the Context of Genetics Studies of Posttraumatic Stress Disorder: A Systematic Review

Background: Posttraumatic stress disorder (PTSD) is a debilitating anxiety disorder. Surveys of the general population suggest that while 50-85% of Americans will experience a traumatic event in their lifetime, only 2-50% will develop PTSD. Why some individuals develop PTSD following trauma exposure while others remain resilient is a central question in the field of trauma research. For more than half a century, the role of genetic influences on PTSD has been considered as a potential vulnerability factor. However, despite the exponential growth of molecular genetic studies over the past decade, limited progress has been made in identifying true genetic variants for PTSD. Methods: In an attempt to aid future genome wide association studies (GWAS), this paper presents a systematic review of 28 genetic association studies of PTSD. Inclusion criteria required that 1) all participants were exposed to Criterion A traumatic events, 2) polymorphisms of relevant genes were genotyped and assessed in relation to participants’ PTSD status, 3) quantitative methods were used, and 4) articles were published in English and in peer-reviewed journals. In the examination of these 28 studies, particular attention was given to variables related to trauma exposure (e.g. number of traumas, type of trauma). Results: Results indicated that most articles did not report on the GxE interaction in the context of PTSD or present data on the main effects of E despite having data available. Furthermore, some studies that did consider the GxE interaction had significant findings, underscoring the importance of examining how genotypes can modify the effect of trauma on PTSD. Additionally, results indicated that only a small number of genes continue to be studied and that there were marked differences in methodologies across studies, which subsequently limited robust conclusions. Conclusions: As trauma exposure is a necessary condition for the PTSD diagnosis, this paper identifies gaps in the current literature as well as provides recommendations for how future GWAS studies can most effectively incorporate trauma exposure data in both the design and analysis phases of studies

Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy.

HIV-associated cryptococcal meningitis is by far the most common cause of adult meningitis in many areas of the world that have high HIV seroprevalence. In most areas in Sub-Saharan Africa, the incidence of cryptococcal meningitis is not decreasing despite availability of antiretroviral therapy, because of issues of adherence and retention in HIV care. In addition, cryptococcal meningitis in HIV-seronegative individuals is a substantial problem: the risk of cryptococcal infection is increased in transplant recipients and other individuals with defects in cell-mediated immunity, and cryptococcosis is also reported in the apparently immunocompetent. Despite therapy, mortality rates in these groups are high. Over the past 5 years, advances have been made in rapid point-of-care diagnosis and early detection of cryptococcal antigen in the blood. These advances have enabled development of screening and pre-emptive treatment strategies aimed at preventing the development of clinical infection in patients with late-stage HIV infection. Progress in optimizing antifungal combinations has been aided by evaluation of the clearance rate of infection by using serial quantitative cultures of cerebrospinal fluid (CSF). Measurement and management of raised CSF pressure, a common complication, is a vital component of care. In addition, we now better understand protective immune responses in HIV-associated cases, immunogenetic predisposition to infection, and the role of immune-mediated pathology in patients with non-HIV associated infection and in the context of HIV-associated immune reconstitution reactions

Future perspectives in melanoma research: meeting report from the "Melanoma Bridge";: Napoli, December 3rd-6th 2014.

The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma

The Genetic Signatures of Noncoding RNAs

The majority of the genome in animals and plants is transcribed in a developmentally regulated manner to produce large numbers of non–protein-coding RNAs (ncRNAs), whose incidence increases with developmental complexity. There is growing evidence that these transcripts are functional, particularly in the regulation of epigenetic processes, leading to the suggestion that they compose a hitherto hidden layer of genomic programming in humans and other complex organisms. However, to date, very few have been identified in genetic screens. Here I show that this is explicable by an historic emphasis, both phenotypically and technically, on mutations in protein-coding sequences, and by presumptions about the nature of regulatory mutations. Most variations in regulatory sequences produce relatively subtle phenotypic changes, in contrast to mutations in protein-coding sequences that frequently cause catastrophic component failure. Until recently, most mapping projects have focused on protein-coding sequences, and the limited number of identified regulatory mutations have been interpreted as affecting conventional cis-acting promoter and enhancer elements, although these regions are often themselves transcribed. Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction. The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions. There is every possibility that many of these variations will alter the interactions between regulatory RNAs and their targets, a prospect that should be borne in mind in future functional analyses