Utility of a buccal swab point-of-care test for the IFNL4 genotype in the era of direct acting antivirals for hepatitis C virus.

BACKGROUND: The CC genotype of the IFNL4 gene is known to be associated with increased Hepatitis C (HCV) cure rates with interferon-based therapy and may contribute to cure with direct acting antivirals. The Genedrive® IFNL4 is a CE marked Point of Care (PoC) molecular diagnostic test, designed for in vitro diagnostic use to provide rapid, real-time detection of IFNL4 genotype status for SNP rs12979860. METHODS: 120 Participants were consented to a substudy comparing IFNL4 genotyping results from a buccal swab analysed on the Genedrive® platform with results generated using the Affymetix UK Biobank array considered to be the gold standard. RESULTS: Buccal swabs were taken from 120 participants for PoC IFNL4 testing and a whole blood sample for genetic sequencing. Whole blood genotyping vs. buccal swab PoC testing identified 40 (33%), 65 (54%), and 15 (13%) had CC, CT and TT IFNL4 genotype respectively. The Buccal swab PoC identified 38 (32%) CC, 64 (53%) CT and 18 (15%) TT IFNL4 genotype respectively. The sensitivity and specificity of the buccal swab test to detect CC vs non-CC was 90% (95% CI 76-97%) and 98% (95% CI 91-100%) respectively. CONCLUSIONS: The buccal swab test was better at correctly identifying non-CC genotypes than CC genotypes. The high specificity of the Genedrive® assay prevents CT/TT genotypes being mistaken for CC, and could avoid patients being identified as potentially 'good responders' to interferon-based therapy

Analysis of IL28B Variants in an Egyptian Population Defines the 20 Kilobases Minimal Region Involved in Spontaneous Clearance of Hepatitis C Virus

Spontaneous clearance of hepatitis C virus (HCV) occurs in ∼30% of acute infections. Host genetics play a major role in HCV clearance, with a strong effect of single nucleotide polymorphisms (SNPs) of the IL28B gene already found in different populations, mostly infected with viral genotypes 1 and 3. Egypt has the highest prevalence of HCV infection in the world, which is mostly due to viral genotype 4. We investigated the role of several IL28B SNPs in HCV spontaneous clearance in an Egyptian population. We selected nine SNPs within the IL28B genomic region covering the linkage disequilibrium (LD) block known to be associated with HCV clearance in European populations. These SNPs were genotyped in 261 HCV-infected Egyptian subjects (130 with spontaneous clearance and 131 with chronic infection). The most associated SNPs were rs12979860 (P = 1.6×10−7) and the non-synonymous IL28B SNP, rs8103142 (P = 1.6×10−7). Interestingly, three SNPs at the two bounds of the region were monomorphic, reducing the size of the LD block in which the causal variants are potentially located to ∼20 kilobases. HCV clearance in Egypt was associated with a region of IL28B smaller than that identified in European populations, and involved the non-synonymous IL28B SNP, rs8103142

Interferon lambda 4 impacts the genetic diversity of hepatitis C virus

Hepatitis C virus (HCV) is a highly variable pathogen that frequently establishes chronic infection. This genetic variability is affected by the adaptive immune response but the contribution of other host factors is unclear. Here, we examined the role played by interferon lambda-4 (IFN-λ4) on HCV diversity; IFN-λ4 plays a crucial role in spontaneous clearance or establishment of chronicity following acute infection. We performed viral genome-wide association studies using human and viral data from 485 patients of white ancestry infected with HCV genotype 3a. We demonstrate that combinations of host genetic variants, which determine IFN-λ4 protein production and activity, influence amino acid variation across the viral polyprotein - not restricted to specific viral proteins or HLA restricted epitopes - and modulate viral load. We also observed an association with viral di-nucleotide proportions. These results support a direct role for IFN-λ4 in exerting selective pressure across the viral genome, possibly by a novel mechanism

Rethinking use-wear analysis and experimentation as applied to the study of past hominin tool use

In prehistoric human populations, technologies played a fundamental role in the acquisition of different resources and are represented in the main daily living activities, such as with bone, wooden, and stone-tipped spears for hunting, and chipped-stone tools for butchering. Considering that paleoanthropologists and archeologists are focused on the study of different processes involved in the evolution of human behavior, investigating how hominins acted in the past through the study of evidence on archeological artifacts is crucial. Thus, investigat ing tool use is of major importance for a comprehensive understanding of all processes that characterize human choices of raw materials, techniques, and tool types. Many functional assumptions of tool use have been based on tool design and morphology according to archeologists’ interpretations and ethnographic observations. Such assumptions are used as baselines when inferring human behavior and have driven an improvement in the methods and techniques employed in functional studies over the past few decades. Here, while arguing that use-wear analysis is a key discipline to assess past hominin tool use and to interpret the organization and variability of artifact types in the archeological record, we aim to review and discuss the current state-of-the-art methods, protocols, and their limitations. In doing so, our discussion focuses on three main topics: (1) the need for fundamental improvements by adopting established methods and techniques from similar research fields, (2) the need to implement and combine different levels of experimentation, and (3) the crucial need to establish standards and protocols in order to improve data quality, standard ization, repeatability, and reproducibility. By adopting this perspective, we believe that studies will increase the reliability and applicability of use-wear methods on tool function. The need for a holistic approach that combines not only use-wear traces but also tool technology, design, curation, durability, and efficiency is also debated and revised. Such a revision is a crucial step if archeologists want to build major inferences on human decision making behavior and biocultural evolution processes.info:eu-repo/semantics/publishedVersio

Exploring the interactions between the human and viral genomes.

Over the last decade, genome-wide association studies led to major advances in identifying human genetic variants associated with infectious disease susceptibility. On the pathogen side, comparable methods are now applied to identify disease-modulating pathogen variants. As host and pathogen variants jointly determine disease outcomes, the most recent development has been to explore simultaneously host and pathogen genomes, through so-called genome-to-genome studies. In this review, we provide some background on the development of genome-to-genome analysis and we detail the first wave of studies in this emerging field, which focused on patients chronically infected with HIV and hepatitis C virus. We also discuss the need for novel statistical methods to better tackle the issues of population stratification and multiple testing. Finally, we speculate on future research areas where genome-to-genome analysis may prove to be particularly effective

Impact of IFNL4 genetic variants on sustained virologic response and viremia in hepatitis C virus genotype 3 patients

Hepatitis C virus (HCV) genotype 3 is very prevalent in Europe and Asia and is associated with worst outcomes than other genotypes. Genetic factors have been associated with HCV infection; however, no extensive genome-wide study has been performed among HCV genotype 3 patients. In this study, using a large cohort of 1,759 patients infected with HCV genotype 3, we explore the role of genetic variants on the response to interferon (IFN) and direct-acting antiviral (DAA) regimens and viremia in a combined candidate gene and genome-wide analysis. We show that genetic variants within the IFN lambda 4 (IFNL4) locus are the major factors associated with the studied traits, accordingly with observations in other HCV genotypes and with comparable effect sizes. In particular, the functional dinucleotide polymorphism rs368234815 was associated with IFN-based sustained virologic response (SVR) [odds ratio (OR) = 1.5, P = 2.3 × 10-7], viremia (beta = -0.23, P = 8.8 × 10-10), and also DAA-based SVR (OR = 1.7; P = 4.2 × 10-4). Our results provide evidence for a role of genetic variants on HCV viremia and SVR, notably DAA-based, in patients infected with HCV genotype 3

Impact of IFNL4 genetic variants on sustained virologic response and viremia in hepatitis C virus genotype 3 patients

Hepatitis C virus (HCV) genotype 3 is very prevalent in Europe and Asia and is associated with worst outcomes than other genotypes. Genetic factors have been associated with HCV infection; however, no extensive genome-wide study has been performed among HCV genotype 3 patients. In this study, using a large cohort of 1,759 patients infected with HCV genotype 3, we explore the role of genetic variants on the response to interferon (IFN) and direct-acting antiviral (DAA) regimens and viremia in a combined candidate gene and genome-wide analysis. We show that genetic variants within the IFN lambda 4 (IFNL4) locus are the major factors associated with the studied traits, accordingly with observations in other HCV genotypes and with comparable effect sizes. In particular, the functional dinucleotide polymorphism rs368234815 was associated with IFN-based sustained virologic response (SVR) [odds ratio (OR) = 1.5, P = 2.3 × 10-7], viremia (beta = -0.23, P = 8.8 × 10-10), and also DAA-based SVR (OR = 1.7; P = 4.2 × 10-4). Our results provide evidence for a role of genetic variants on HCV viremia and SVR, notably DAA-based, in patients infected with HCV genotype 3

The operational cloud retrieval algorithms from TROPOMI on board Sentinel-5 Precursor

This paper presents the operational cloud retrieval algorithms for the TROPOspheric Monitoring Instrument (TROPOMI) on board the European Space Agency Sentinel-5 Precursor (S5P) mission scheduled for launch in 2017. Two algorithms working in tandem are used for retrieving cloud properties: OCRA (Optical Cloud Recognition Algorithm) and ROCINN (Retrieval of Cloud Information using Neural Networks). OCRA retrieves the cloud fraction using TROPOMI measurements in the ultraviolet (UV) and visible (VIS) spectral regions, and ROCINN retrieves the cloud top height (pressure) and optical thickness (albedo) using TROPOMI measurements in and around the oxygen A-band in the near infrared (NIR). Cloud parameters from TROPOMI/S5P will be used not only for enhancing the accuracy of trace gas retrievals but also for extending the satellite data record of cloud information derived from oxygen A-band measurements, a record initiated with the Global Ozone Monitoring Experiment (GOME) on board the second European Remote-Sensing Satellite (ERS-2) over 20 years ago. The OCRA and ROCINN algorithms are integrated in the S5P operational processor UPAS (Universal Processor for UV/VIS/NIR Atmospheric Spectrometers), and we present here UPAS cloud results using the Ozone Monitoring Instrument (OMI) and GOME-2 measurements. In addition, we examine anticipated challenges for the TROPOMI/S5P cloud retrieval algorithms, and we discuss the future validation needs for OCRA and ROCINN

Modifier locus of the skeletal muscle involvement in Emery–Dreifuss muscular dystrophy

International audienceAutosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in LMNA gene encoding lamins A and C. The disease is characterized by early onset joint contractures during childhood associated with humero-peroneal muscular wasting and weakness, and by the development of a cardiac disease in adulthood. Important intra-familial variability characterized by a wide range of age at onset of myopathic symptoms (AOMS) has been recurrently reported, suggesting the contribution of a modifier gene. Our objective was to identify a modifier locus of AOMS in relation with the LMNA mutation. To map the modifier locus, we genotyped 291 microsatellite markers in 59 individuals of a large French family, where 19 patients carrying the same LMNA mutation, exhibited wide range of AOMS. We performed Bayesian Markov Chain Monte Carlo-based joint segregation and linkage methods implemented in the Loki software, and detected a strong linkage signal on chromosome 2 between markers D2S143 and D2S2244 (211 cM) with a Bayes factor of 28.7 (empirical p value = 0.0032). The linked region harbours two main candidate genes, DES and MYL1 encoding desmin and light chain of myosin. Importantly, the impact of the genotype on the phenotype for this locus showed an overdominant effect with AOMS 2 years earlier for the homozygotes of the rare allele and 37 years earlier for the heterozygotes than the homozygotes for the common allele. These results provide important highlights for the natural history and for the physiopathology of Emery-Dreifuss muscular dystrophy

Impact of IFNL4 genotype on interferon-stimulated gene expression during daa therapy for Hepatitis C

New directly acting antivirals (DAAs) provide very high cure rates in most patients infected by hepatitis C virus (HCV). However, some patient groups have been relatively harder to treat including those with cirrhosis or infected with HCV genotype 3. In the recent BOSON trial, genotype 3, cirrhotic patients receiving a 16 week course of sofosbuvir and ribavirin had a sustained virologic response rate (SVR) of around 50%. In cirrhotic patients, IFNL4 CC genotype was significantly associated with SVR. This genotype was also associated with a lower interferon‐stimulated gene (ISG) signature in peripheral blood and in liver at baseline. Unexpectedly, patients with the CC genotype showed a dynamic increase in ISG expression between weeks 4 and 16 of DAA therapy, while the reverse was true for non‐CC patients. These data provide an important dynamic link between host genotype and phenotype in HCV therapy also potentially relevant to naturally acquired infection