Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin

BIOFRAG: A new database for analysing BIOdiversity responses to forest FRAGmentation

Habitat fragmentation studies are producing inconsistent and complex results across which it is nearly impossible to synthesise. Consistent analytical techniques can be applied to primary datasets, if stored in a flexible database that allows simple data retrieval for subsequent analyses. Method: We developed a relational database linking data collected in the field to taxonomic nomenclature, spatial and temporal plot attributes and further environmental variables (e.g. information on biogeographic region. Typical field assessments include measures of biological variables (e.g. presence, abundance, ground cover) of one species or a set of species linked to a set of plots in fragments of a forested landscape. Conclusion: The database currently holds records of 5792 unique species sampled in 52 landscapes in six of eight biogeographic regions: mammals 173, birds 1101, herpetofauna 284, insects 2317, other arthropods: 48, plants 1804, snails 65. Most species are found in one or two landscapes, but some are found in four. Using the huge amount of primary data on biodiversity response to fragmentation becomes increasingly important as anthropogenic pressures from high population growth and land demands are increasing. This database can be queried to extract data for subsequent analyses of the biological response to forest fragmentation with new metrics that can integrate across the components of fragmented landscapes. Meta-analyses of findings based on consistent methods and metrics will be able to generalise over studies allowing inter-comparisons for unified answers. The database can thus help researchers in providing findings for analyses of trade-offs between land use benefits and impacts on biodiversity and to track performance of management for biodiversity conservation in human-modified landscapes.Fil: Pfeifer, Marion. Imperial College London; Reino UnidoFil: Lefebvre, Veronique. Imperial College London; Reino UnidoFil: Gardner, Toby A.. Stockholm Environment Institute; SueciaFil: Arroyo Rodríguez, Víctor. Universidad Nacional Autónoma de México; MéxicoFil: Baeten, Lander. University of Ghent; BélgicaFil: Banks Leite, Cristina. Imperial College London; Reino UnidoFil: Barlow, Jos. Lancaster University; Reino UnidoFil: Betts, Matthew G.. State University of Oregon; Estados UnidosFil: Brunet, Joerg. Swedish University of Agricultural Sciences; SueciaFil: Cerezo Blandón, Alexis Mauricio. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Métodos Cuantitativos y Sistemas de Información; ArgentinaFil: Cisneros, Laura M.. University of Connecticut; Estados UnidosFil: Collard, Stuart. Nature Conservation Society of South Australia; AustraliaFil: D´Cruze, Neil. The World Society for the Protection of Animals; Reino UnidoFil: Da Silva Motta, Catarina. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: Duguay, Stephanie. Carleton University; CanadáFil: Eggermont, Hilde. University of Ghent; BélgicaFil: Eigenbrod, Félix. University of Southampton; Reino UnidoFil: Hadley, Adam S.. State University of Oregon; Estados UnidosFil: Hanson, Thor R.. No especifíca;Fil: Hawes, Joseph E.. University of East Anglia; Reino UnidoFil: Heartsill Scalley, Tamara. United State Department of Agriculture. Forestry Service; Puerto RicoFil: Klingbeil, Brian T.. University of Connecticut; Estados UnidosFil: Kolb, Annette. Universitat Bremen; AlemaniaFil: Kormann, Urs. Universität Göttingen; AlemaniaFil: Kumar, Sunil. State University of Colorado - Fort Collins; Estados UnidosFil: Lachat, Thibault. Swiss Federal Institute for Forest; SuizaFil: Lakeman Fraser, Poppy. Imperial College London; Reino UnidoFil: Lantschner, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche; ArgentinaFil: Laurance, William F.. James Cook University; AustraliaFil: Leal, Inara R.. Universidade Federal de Pernambuco; BrasilFil: Lens, Luc. University of Ghent; BélgicaFil: Marsh, Charles J.. University of Leeds; Reino UnidoFil: Medina Rangel, Guido F.. Universidad Nacional de Colombia; ColombiaFil: Melles, Stephanie. University of Toronto; CanadáFil: Mezger, Dirk. Field Museum of Natural History; Estados UnidosFil: Oldekop, Johan A.. University of Sheffield; Reino UnidoFil: Overal , Williams L.. Museu Paraense Emílio Goeldi. Departamento de Entomologia; BrasilFil: Owen, Charlotte. Imperial College London; Reino UnidoFil: Peres, Carlos A.. University of East Anglia; Reino UnidoFil: Phalan, Ben. University of Southampton; Reino UnidoFil: Pidgeon, Anna Michle. University of Wisconsin; Estados UnidosFil: Pilia, Oriana. Imperial College London; Reino UnidoFil: Possingham, Hugh P.. Imperial College London; Reino Unido. The University Of Queensland; AustraliaFil: Possingham, Max L.. No especifíca;Fil: Raheem, Dinarzarde C.. Royal Belgian Institute of Natural Sciences; Bélgica. Natural History Museum; Reino UnidoFil: Ribeiro, Danilo B.. Universidade Federal do Mato Grosso do Sul; BrasilFil: Ribeiro Neto, Jose D.. Universidade Federal de Pernambuco; BrasilFil: Robinson, Douglas W.. State University of Oregon; Estados UnidosFil: Robinson, Richard. Manjimup Research Centre; AustraliaFil: Rytwinski, Trina. Carleton University; CanadáFil: Scherber, Christoph. Universität Göttingen; AlemaniaFil: Slade, Eleanor M.. University of Oxford; Reino UnidoFil: Somarriba, Eduardo. Centro Agronómico Tropical de Investigación y Enseñanza; Costa RicaFil: Stouffer, Philip C.. State University of Louisiana; Estados UnidosFil: Struebig, Matthew J.. University of Kent; Reino UnidoFil: Tylianakis, Jason M.. University College London; Estados Unidos. Imperial College London; Reino UnidoFil: Teja, Tscharntke. Universität Göttingen; AlemaniaFil: Tyre, Andrew J.. Universidad de Nebraska - Lincoln; Estados UnidosFil: Urbina Cardona, Jose N.. Pontificia Universidad Javeriana; ColombiaFil: Vasconcelos, Heraldo L.. Universidade Federal de Uberlandia; BrasilFil: Wearn, Oliver. Imperial College London; Reino Unido. The Zoological Society of London; Reino UnidoFil: Wells, Konstans. University of Adelaide; AustraliaFil: Willig, Michael R.. University of Connecticut; Estados UnidosFil: Wood, Eric. University of Wisconsin; Estados UnidosFil: Young, Richard P.. Durrell Wildlife Conservation Trust; Reino UnidoFil: Bradley, Andrew V.. Imperial College London; Reino UnidoFil: Ewers, Robert M.. Imperial College London; Reino Unid

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

BIOFRAG - a new database for analyzing BIOdiversity responses to forest FRAGmentation

Peer reviewe

BIOFRAG – a new database for analyzing BIOdiversity responses to forest FRAGmentation

Habitat fragmentation studies have produced complex results that are challenging to synthesize. Inconsistencies among studies may result from variation in the choice of landscape metrics and response variables, which is often compounded by a lack of key statistical or methodological information. Collating primary datasets on biodiversity responses to fragmentation in a consistent and flexible database permits simple data retrieval for subsequent analyses. We present a relational database that links such field data to taxonomic nomenclature, spatial and temporal plot attributes, and environmental characteristics. Field assessments include measurements of the response(s) (e.g., presence, abundance, ground cover) of one or more species linked to plots in fragments within a partially forested landscape. The database currently holds 9830 unique species recorded in plots of 58 unique landscapes in six of eight realms: mammals 315, birds 1286, herptiles 460, insects 4521, spiders 204, other arthropods 85, gastropods 70, annelids 8, platyhelminthes 4, Onychophora 2, vascular plants 2112, nonvascular plants and lichens 320, and fungi 449. Three landscapes were sampled as long-term time series (>10 years). Seven hundred and eleven species are found in two or more landscapes. Consolidating the substantial amount of primary data available on biodiversity responses to fragmentation in the context of land-use change and natural disturbances is an essential part of understanding the effects of increasing anthropogenic pressures on land. The consistent format of this database facilitates testing of generalizations concerning biologic responses to fragmentation across diverse systems and taxa. It also allows the re-examination of existing datasets with alternative landscape metrics and robust statistical methods, for example, helping to address pseudo-replication problems. The database can thus help researchers in producing broad syntheses of the effects of land use. The database is dynamic and inclusive, and contributions from individual and large-scale data-collection efforts are welcome.Keywords: Species turnover, Data sharing, Database, Global change, Landscape metrics, Edge effects, Forest fragmentation, Matrix contrast, Bioinformatic

Serum NT/CT SIRT1 ratio reflects early osteoarthritis and chondrosenescence

Abstract Objective: Previous work has established that the deacetylase sirtuin-1 (SIRT1) is cleaved by cathepsin B in chondrocytes subjected to proinflammatory stress, yielding a stable but inactive N-terminal (NT) polypeptide (75SIRT1) and a C-terminal (CT) fragment. The present work examined if chondrocyte-derived NT-SIRT1 is detected in serum and may serve as an investigative and exploratory biomarker of osteoarthritis (OA). Methods: We developed a novel ELISA assay to measure the ratio of NT to CT of SIRT1 in the serum of human individuals and mice subjected to post-traumatic OA (PTOA) or age-dependent OA (ADOA). We additionally monitored NT/CT SIRT1 in mice subject to ADOA/PTOA followed by senolytic clearance. Human chondrosenescent and non-senescent chondrocytes were exposed to cytokines and analysed for apoptosis and NT/CT SIRT1 ratio in conditioned medium. Results: Wild-type mice with PTOA or ADOA of moderate severity exhibited increased serum NT/CT SIRT1 ratio. In contrast, this ratio remained low in cartilage-specific Sirt1 knockout mice despite similar or increased PTOA and ADOA severity. Local clearance of senescent chondrocytes from old mice with post-traumatic injury resulted in a lower NT/CT ratio and reduced OA severity. While primary chondrocytes exhibited NT/CT ratio increased in conditioned media after prolonged cytokine stimulation, this increase was not evident in cytokine-stimulated chondrosenescent cells. Finally, serum NT/CT ratio was elevated in humans with early-stage OA. Conclusions: Increased levels of serum NT/CT SIRT1 ratio correlated with moderate OA in both mice and humans, stemming at least in part from non-senescent chondrocyte apoptosis, possibly a result of prolonged inflammatory insult

Sox11 gene disruption causes congenital anomalies of the kidney and urinary tract (CAKUT)

Congenital abnormalities of the kidney and the urinary tract (CAKUT) belong to the most common birth defects in human, but the molecular basis for the majority of CAKUT patients remains unknown. Here we show that the transcription factor SOX11 is a crucial regulator of kidney development. SOX11 is expressed in both mesenchymal and epithelial components of the early kidney anlagen. Deletion of Sox11 in mice causes an extension of the domain expressing Gdnf within rostral regions of the nephrogenic cord and results in duplex kidney formation. On the molecular level SOX11 directly binds and regulates a locus control region of the protocadherin B cluster. At later stages of kidney development, SOX11 becomes restricted to the intermediate segment of the developing nephron where it is required for the elongation of Henle's loop. Finally, mutation analysis in a cohort of patients suffering from CAKUT identified a series of rare SOX11 variants, one of which interferes with the transactivation capacity of the SOX11 protein. Taken together these data demonstrate a key role for SOX11 in normal kidney development and may suggest that variants in this gene predispose to CAKUT in humans

Dolutegravir-based dual maintenance regimens combined with lamivudine/emtricitabine or rilpivirine: risk of virological failure in a real-life setting

International audienceBackground Maintenance ART with dolutegravir-based dual regimens have proved their efficacy among HIV-1-infected subjects in randomized trials. However, real-life data are scarce, with limited populations and follow-up. Objectives We assessed virological failure (VF) and resistance-associated mutations (RAMs) on dolutegravir maintenance regimens in combination with rilpivirine or with lamivudine or emtricitabine (xTC) and analysed the factors associated with VF. Methods Between 2014 and 2018, all HIV-1-infected adults included in the Dat’AIDS cohort and starting dolutegravir/rilpivirine or dolutegravir/xTC as a maintenance dolutegravir-based dual regimen were selected. VF was defined as two consecutive HIV RNA values &gt;50 copies/mL or a single value &gt;400 copies/mL. We compared cumulative genotypes before initiation of a maintenance dolutegravir-based dual regimen with genotype at VF. Results We analysed 1374 subjects (799 on dolutegravir/rilpivirine and 575 on dolutegravir/xTC) with a median follow-up of 20 months (IQR = 11–31) and 19 months (IQR = 11–31), respectively. VF occurred in 3.8% (n = 30) of dolutegravir/rilpivirine subjects and 2.6% (n = 15) of dolutegravir/xTC subjects. Among subjects receiving dolutegravir/rilpivirine, two genotypes harboured emerging RAMs at VF: E138K on NNRTI (n = 1); and E138K+K101E on NNRTI and N155H on INSTI (n = 1). Among subjects receiving dolutegravir/xTC, no new RAM was detected. The only predictive factor of VF on dolutegravir/rilpivirine was the history of failure on an NNRTI-based regimen (adjusted HR = 2.97, 95% CI = 1.28–6.93). No factor was associated with VF on dolutegravir/xTC. Conclusions In this large real-life cohort, dolutegravir/rilpivirine and dolutegravir/xTC sustained virological suppression and were associated with a low rate of VF and RAM emergence. Careful virological screening is essential before switching to dolutegravir/rilpivirine in virologically suppressed patients with a history of NNRTI therapy

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old