Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies ...(GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.
Hepatitis C virus (HCV) exhibits high genetic diversity, characterized by regional variations in genotype prevalence. This poses a challenge to the improved development of vaccines and pan‐genotypic ...treatments, which require the consideration of global trends in HCV genotype prevalence. Here we provide the first comprehensive survey of these trends. To approximate national HCV genotype prevalence, studies published between 1989 and 2013 reporting HCV genotypes are reviewed and combined with overall HCV prevalence estimates from the Global Burden of Disease (GBD) project. We also generate regional and global genotype prevalence estimates, inferring data for countries lacking genotype information. We include 1,217 studies in our analysis, representing 117 countries and 90% of the global population. We calculate that HCV genotype 1 is the most prevalent worldwide, comprising 83.4 million cases (46.2% of all HCV cases), approximately one‐third of which are in East Asia. Genotype 3 is the next most prevalent globally (54.3 million, 30.1%); genotypes 2, 4, and 6 are responsible for a total 22.8% of all cases; genotype 5 comprises the remaining <1%. While genotypes 1 and 3 dominate in most countries irrespective of economic status, the largest proportions of genotypes 4 and 5 are in lower‐income countries. Conclusion: Although genotype 1 is most common worldwide, nongenotype 1 HCV cases—which are less well served by advances in vaccine and drug development—still comprise over half of all HCV cases. Relative genotype proportions are needed to inform healthcare models, which must be geographically tailored to specific countries or regions in order to improve access to new treatments. Genotype surveillance data are needed from many countries to improve estimates of unmet need. (Hepatology 2015;61:77–87)
Background. Achievement of a sustained virologic response (SVR) after treatment for Hepatitis C infection is associated with improved outcomes. This meta-analysis aimed to determine the impact of SVR ...on long-term mortality risk compared with nonresponders in a range of populations. Methods. An electronic search identified all studies assessing all-cause mortality in SVR and non-SVR patients. Eligible articles were stratified into general, cirrhotic, and populations coinfected with human immunodeficiency virus. The adjusted hazard ratio (95% confidence interval CI for mortality in patients achieving SVR vs non-SVR, and pooled estimates for the 5-year mortality in each group were calculated. Results. 31 studies (n = 33 360) were identified as suitable for inclusion. Median follow-up time was 5.4 years (interquartile range, 4.9–7.5) across all studies. The adjusted hazard ratio of mortality for patients achieving SVR vs non-SVR was 0.50 (95% CI, .37–.67) in the general population, 0.26 (95% CI, .18–.74) in the cirrhotic group, and 0.21 (.10–.45) in the coinfected group. The pooled 5-year mortality rates were significantly lower for patients achieving SVR compared with non-SVR in all 3 populations. Conclusions. The results suggest that there is a significant survival benefit of achieving an SVR compared with unsuccessful treatment in a range of populations infected with hepatitis C virus.
Identification of the causative organism(s) in periprosthetic joint infection (PJI) is a challenging task. The shortcomings of traditional cultures have been emphasized in recent literature, ...culminating in a clinical entity known as “culture-negative PJI.” Amidst the growing burden of biofilm infections that are inherently difficult to culture, the field of clinical microbiology has seen a paradigm shift from culture-based to molecular-based methods. These novel techniques hold much promise in the demystification of culture-negative PJI and revolutionization of the microbiology laboratory. This article outlines the clinical implications of culture-negative PJI, common causes of this diagnostic conundrum, established strategies to improve culture yield, and newer molecular techniques to detect infectious organisms.
Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ...ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity.
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•Genetic ablation of ILC2s impairs type-2 immunity•MHCII-expressing ILC2s potentiate Th2 responses•IL-2 from T cells promotes ILC2 proliferation and expression of type-2 cytokines•MHCII and IL-13 expression by ILC2s is important for N. brasiliensis expulsion
Type-2 innate lymphoid cells proliferate and release interleukin-13 during protective immunity to helminth infection and detrimentally during allergy and asthma. McKenzie and colleagues establish that these activities are potentiated through an MHC class II-mediated dialogue with T cells.
The fate of nano zerovalent iron (nZVI) during subsurface injection was examined using carboxymethylcellulose (CMC) stabilized nZVI in a very large three-dimensional physical model aquifer with ...detailed monitoring using multiple, complementary detection methods. A fluorescein tracer test in the aquifer plus laboratory column data suggested that the very-aggressive flow conditions necessary to achieve 2.5 m of nZVI transport could be obtained using a hydraulically constrained flow path between injection and extraction wells. However, total unoxidized nZVI was transported only about 1 m and <2% of the injected nZVI concentration reached that distance. The experimental data also indicated that groundwater flow changed during injection, likely due to hydrogen bubble formation, which diverted the nZVI away from the targeted flow path. The leading edge of the iron plume became fully oxidized during transport. However, within the plume, oxidation of nZVI decreased in a fashion consistent with progressive depletion of aquifer “reductant demand”. To directly quantify the extent of nZVI transport, a spectrophotometric method was developed, and the results indicated that deployment of unoxidized nZVI for groundwater remediation will likely be difficult.
We observe signatures of radial and angular roton excitations around a droplet crystallization transition in dipolar Bose-Einstein condensates. In situ measurements are used to characterize the ...density fluctuations near this transition. The static structure factor is extracted and used to identify the radial and angular roton excitations by their characteristic symmetries. These fluctuations peak as a function of the interaction strength indicating the crystallization transition of the system. We compare our observations to a theoretically calculated excitation spectrum allowing us to connect the crystallization mechanism with the softening of the angular roton modes.
Summary
Antiviral vaccines have been the most successful biomedical intervention for preventing epidemic viral disease. Vaccination for smallpox in humans and rinderpest in cattle was the basis for ...disease eradication, and recent progress in polio eradication is promising. Although early vaccines were developed empirically by passage in live animals or eggs, more recent vaccines have been developed because of the advent of new technologies, particularly cell culture and molecular biology. Recent technological advances in gene delivery and expression, nanoparticles, protein manufacturing, and adjuvants have created the potential for new vaccine platforms that may provide solutions for vaccines against viral pathogens for which no interventions currently exist. In addition, the technological convergence of human monoclonal antibody isolation, structural biology, and high‐throughput sequencing is providing new opportunities for atomic‐level immunogen design. Selection of human monoclonal antibodies can identify immunodominant antigenic sites associated with neutralization and provide reagents for stabilizing and solving the structure of viral surface proteins. Understanding the structural basis for neutralization can guide selection of vaccine targets. Deep sequencing of the antibody repertoire and defining the ontogeny of the desired antibody responses can reveal the junctional recombination and somatic mutation requirements for B‐cell recognition and affinity maturation. Collectively, this information will provide new strategic approaches for selecting vaccine antigens, formulations, and regimens. Moreover, it creates the potential for rational vaccine design and establishing a catalogue of vaccine technology platforms that would be effective against any given family or class of viral pathogens and improve our readiness to address new emerging viral threats.
Following an acute myocardial infarction (MI), patients with persistently elevated biomarkers of inflammation, in particular C-reactive protein (CRP), are at significantly increased risk of further ...cardiovascular events. Colchicine is a unique anti-inflammatory medication that has shown promise in reducing such events in patients with stable coronary heart disease. The current study tested the ability of low dose colchicine to reduce CRP levels at 30 days after an acute MI, a key marker of future outcome, and its safety and tolerability in this setting.
We conducted a randomized, double-blind, trial of low-dose colchicine (0.5 mg daily) or matching placebo in 237 patients admitted with an acute MI. The primary end-point was the proportion of patients with a residual high sensitivity CRP level ≥2 mg/L after 30 days of treatment, a threshold associated with a worse prognosis.
At 30-day follow-up, 44% of patients treated with colchicine had a CRP level ≥2 mg/L compared to 50% of those randomized to placebo (P = .35) and the median CRP in patients randomized to colchicine was 1.6 mg/L (interquartile range IQR 0.7–3.5) compared to 2.0 mg/L (IQR 0.9–4.0) in patients randomized to placebo (P = .11). The median absolute reduction in CRP levels was −4.3 mg/L (IQR −1.1 to −14.1) among colchicine treated patients and −3.3 mg/L (IQR −0.9 to −14.4, P = .44) in placebo treated patients. The relative reduction was a fall of 78% compared to a fall of 64% (P = .09). Low dose colchicine was well tolerated and did not reduce compliance with other secondary preventative medications at 30-days.
Treatment with low dose colchicine was safe and well tolerated, but was not associated with a significantly increased likelihood of achieving a CRP level <2 mg/L or lower absolute levels of CRP 30 days after an acute MI.
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