Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe

Background: HBsAg immune-escape mutations can favor HBV-transmission also in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. Stop-codons can enhance HBV oncogenic-properties. Furthermore, as a consequence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can derive from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immune-associated escape mutations, and stop-codons in HBsAg in chronically HBV-infected patients experiencing nucleos(t)ide analogues (NA) in Europe. Methods: This study analyzed 828 chronically HBV-infected European patients exposed to ≥ 1 NA, with detectable HBV-DNA and with an available HBsAg-sequence. The immune-associated escape mutations and the NA-induced immune-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204I, and rtV173L) were retrieved from literature and examined. Mutations were defined as an aminoacid substitution with respect to a genotype A or D reference sequence. Results: At least one immune-associated escape mutation was detected in 22.1% of patients with rising temporal-trend. By multivariable-analysis, genotype-D correlated with higher selection of ≥ 1 immune-associated escape mutation (OR[95%CI]:2.20[1.32-3.67], P = 0.002). In genotype-D, the presence of ≥ 1 immune-associated escape mutations was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3% P = 0.012). Result confirmed by ana

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Measurements of angular distance and momentum ratio distributions in three-jet and Z plus two-jet final states in pp collisions

Collinear (small-angle) and large-angle, as well as soft and hard radiations are investigated in three-jet and Z + two-jet events collected in proton-proton collisions at the LHC. The normalized production cross sections are measured as a function of the ratio of transverse momenta of two jets and their angular separation. The measurements in the three-jet and Z + two-jet events are based on data collected at a center-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 19.8 fb(-1). The Z + two-jet events are reconstructed in the dimuon decay channel of the Z boson. The three-jet measurement is extended to include root s = 13 TeV data corresponding to an integrated luminosity of 2.3 fb(-1). The results are compared to predictions from event generators that include parton showers, multiple parton interactions, and hadronization. The collinear and soft regions are in general well described by parton showers, whereas the regions of large angular separation are often best described by calculations using higher-order matrix elements.Peer reviewe

Integrative epigenomics in Sjögren's syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Primary Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune populati

Acute heart failure congestion and perfusion status – impact of the clinical classification on in-hospital and long-term outcomes; insights from the ESC-EORP-HFA Heart Failure Long-Term Registry

Aims: Classification of acute heart failure (AHF) patients into four clinical profiles defined by evidence of congestion and perfusion is advocated by the 2016 European Society of Cardiology (ESC)guidelines. Based on the ESC-EORP-HFA Heart Failure Long-Term Registry, we compared differences in baseline characteristics, in-hospital management and outcomes among congestion/perfusion profiles using this classification. Methods and results: We included 7865 AHF patients classified at admission as: ‘dry-warm’ (9.9%), ‘wet-warm’ (69.9%), ‘wet-cold’ (19.8%) and ‘dry-cold’ (0.4%). These groups differed significantly in terms of baseline characteristics, in-hospital management and outcomes. In-hospital mortality was 2.0% in ‘dry-warm’, 3.8% in ‘wet-warm’, 9.1% in ‘dry-cold’ and 12.1% in ‘wet-cold’ patients. Based on clinical classification at admission, the adjusted hazard ratios (95% confidence interval) for 1-year mortality were: ‘wet-warm’ vs. ‘dry-warm’ 1.78 (1.43–2.21) and ‘wet-cold’ vs. ‘wet-warm’ 1.33 (1.19–1.48). For profiles resulting from discharge classification, the adjusted hazard ratios (95% confidence interval) for 1-year mortality were: ‘wet-warm’ vs. ‘dry-warm’ 1.46 (1.31–1.63) and ‘wet-cold’ vs. ‘wet-warm’ 2.20 (1.89–2.56). Among patients discharged alive, 30.9% had residual congestion, and these patients had higher 1-year mortality compared to patients discharged without congestion (28.0 vs. 18.5%). Tricuspid regurgitation, diabetes, anaemia and high New York Heart Association class were independently associated with higher risk of congestion at discharge, while beta-blockers at admission, de novo heart failure, or any cardiovascular procedure during hospitalization were associated with lower risk of residual congestion. Conclusion: Classification based on congestion/perfusion status provides clinically relevant information at hospital admission and discharge. A better understanding of the clinical course of the two entities could play an important role towards the implementation of targeted strategies that may improve outcomes. © 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiolog

Evolution of genes and genomes on the Drosophila phylogeny

Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species

Performance of Prognostic Risk Scores in Chronic Heart Failure Patients Enrolled in the European Society of Cardiology Heart Failure Long-Term Registry

Objectives: This study compared the performance of major heart failure (HF) risk models in predicting mortality and examined their utilization using data from a contemporary multinational registry. Background: Several prognostic risk scores have been developed for ambulatory HF patients, but their precision is still inadequate and their use limited. Methods: This registry enrolled patients with HF seen in participating European centers between May 2011 and April 2013. The following scores designed to estimate 1- to 2-year all-cause mortality were calculated in each participant: CHARM (Candesartan in Heart Failure-Assessment of Reduction in Mortality), GISSI-HF (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico-Heart Failure), MAGGIC (Meta-analysis Global Group in Chronic Heart Failure), and SHFM (Seattle Heart Failure Model). Patients with hospitalized HF (n = 6,920) and ambulatory HF patients missing any variable needed to estimate each score (n = 3,267) were excluded, leaving a final sample of 6,161 patients. Results: At 1-year follow-up, 5,653 of 6,161 patients (91.8%) were alive. The observed-to-predicted survival ratios (CHARM: 1.10, GISSI-HF: 1.08, MAGGIC: 1.03, and SHFM: 0.98) suggested some overestimation of mortality by all scores except the SHFM. Overprediction occurred steadily across levels of risk using both the CHARM and the GISSI-HF, whereas the SHFM underpredicted mortality in all risk groups except the highest. The MAGGIC showed the best overall accuracy (area under the curve [AUC] = 0.743), similar to the GISSI-HF (AUC = 0.739; p = 0.419) but better than the CHARM (AUC = 0.729; p = 0.068) and particularly better than the SHFM (AUC = 0.714; p = 0.018). Less than 1% of patients received a prognostic estimate from their enrolling physician. Conclusions: Performance of prognostic risk scores is still limited and physicians are reluctant to use them in daily practice. The need for contemporary, more precise prognostic tools should be considered

Measurement of CP asymmetries in D(s)+→ηπ+ {D}_{(s)}^{+}\to \eta {\pi}^{+} and D(s)+→η′π+ {D}_{(s)}^{+}\to {\eta}^{\prime }{\pi}^{+} decays

Searches for CP violation in the decays ${D}_{(s)}^{+}\to \eta {\pi}^{+}$ and ${D}_{(s)}^{+}\to {\eta}^{\prime }{\pi}^{+}$ are performed using pp collision data corresponding to 6 fb$^{−1}$ of integrated luminosity collected by the LHCb experiment. The calibration channels ${D}_{(s)}^{+}\to \phi {\pi}^{+}$ are used to remove production and detection asymmetries. The resulting CP-violating asymmetries are${\displaystyle \begin{array}{l}{\mathcal{A}}^{CP}=\left({D}^{+}\to \eta {\pi}^{+}\right)=\left(0.34\pm 0.66\pm 0.16\pm 0.05\right)\%,\\ {}{\mathcal{A}}^{CP}=\left({D}_s^{+}\to \eta {\pi}^{+}\right)=\left(0.32\pm 0.51\pm 0.12\right)\%,\\ {}\begin{array}{l}{\mathcal{A}}^{CP}=\left({D}^{+}\to {\eta}^{\prime }{\pi}^{+}\right)=\left(0.49\pm 0.18\pm 0.06\pm 0.05\right)\%,\\ {}{\mathcal{A}}^{CP}=\left({D}_s^{+}\to {\eta}^{\prime }{\pi}^{+}\right)=\left(0.01\pm 0.12\pm 0.08\right)\%,\end{array}\end{array}}$where the first uncertainty is statistical, the second is systematic and the third, relevant for the D$^{+}$ channels, is due to the uncertainty on ${\mathcal{A}}^{CP}=\left({D}^{+}\to \phi {\pi}^{+}\right)$. These measurements, currently the most precise for three of the four channels considered, are consistent with the absence of CP violation. A combination of these results with previous LHCb measurements is presented.[graphic not available: see fulltext]Searches for $CP$ violation in the decays $D^+_{(s)}\rightarrow \eta \pi^+$ and $D^+_{(s)}\rightarrow \eta^{\prime} \pi^+$ are performed using $pp$ collision data corresponding to 6 fb$^{-1}$ of integrated luminosity collected by the LHCb experiment. The calibration channels $D^+_{(s)}\rightarrow \phi \pi^+$ are used to remove production and detection asymmetries. The resulting $CP$-violating asymmetries are $A^{CP}(D^+ \rightarrow \eta \pi^+) = (0.34 \pm 0.66 \pm 0.16 \pm 0.05)\%$, $A^{CP}(D^+_s \rightarrow \eta \pi^+) = (0.32 \pm 0.51 \pm 0.12)\%$, $A^{CP}(D^+ \rightarrow \eta^{\prime} \pi^+) = (0.49 \pm 0.18 \pm 0.06 \pm 0.05)\%$, $A^{CP}(D^+_s \rightarrow \eta^{\prime} \pi^+) = (0.01 \pm 0.12 \pm 0.08)\%$, where the first uncertainty is statistical, the second is systematic and the third, relevant for the $D^+$ channels, is due to the uncertainty on $A^{CP}(D^+ \to \phi \pi^+)$. These measurements, currently the most precise for three of the four channels considered, are consistent with the absence of $CP$ violation. A combination of these results with previous LHCb measurements is presented

Observation of the Bs0 ⁣→D∗+D∗−B^0_s\!\to D^{*+}D^{*-} decay

International audienceThe first observation of the ${B}_s^0$→ D$^{∗+}$D$^{∗−}$ decay and the measurement of its branching ratio relative to the B$^{0}$→ D$^{∗+}$D$^{∗−}$ decay are presented. The data sample used corresponds to an integrated luminosity of 9 fb$^{−1}$ of proton-proton collisions recorded by the LHCb experiment at centre-of-mass energies of 7, 8 and 13 TeV between 2011 and 2018. The decay is observed with more than 10 standard deviations and the time-integrated ratio of branching fractions is determined to be$\frac{\mathcal{B}\left({B}_s^0\to {D}^{\ast +}{D}^{\ast -}\right)}{\mathcal{B}\left({B}^0\to {D}^{\ast +}{D}^{\ast -}\right)}=0.269\pm 0.032\pm 0.011\pm 0.008,$where the first uncertainty is statistical, the second systematic and the third due to the uncertainty of the fragmentation fraction ratio f$_{s}$/f$_{d}$. The ${B}_s^0$→ D$^{*+}$D$^{*−}$ branching fraction is calculated to be$\mathcal{B}\left({B}_s^0\to {D}^{\ast +}{D}^{\ast -}\right)=\left(2.15\pm 0.26\pm 0.09\pm 0.06\pm 0.16\right)\times {10}^{-4},$where the fourth uncertainty is due to the B$^{0}$→ D$^{*+}$D$^{*−}$ branching fraction. These results are calculated using the average ${B}_s^0$ meson lifetime in simulation. Correction factors are reported for scenarios where either a purely heavy or a purely light ${B}_s^0$ eigenstate is considered.[graphic not available: see fulltext