Lamivudine and Entecavir for Acute Hepatitis B: A Systematic Review and Meta-Analysis.

BACKGROUND: Acute hepatitis B infection is associated with severe liver disease and chronic sequelae in some cases. The purpose of this review was to determine the efficacy of nucleoside analogues (NA) (lamivudine versus entecavir) compared to placebo or no intervention for treating acute primary HBV infection. METHODS: A meta-analysis for drug intervention was performed, following a fixed-effect model. Randomized controlled trials (RCTs) and quasi-randomized studies that evaluated the outcomes of NA in acute hepatitis B infection were included. The following outcomes were considered: virological cure (PCR negative), elimination of acute infection (seroconversion of HBsAg), mortality, and serious adverse events. RESULTS: Five trials with 627 adult participants with severe acute hepatitis B defined by biochemical and serologic parameters were included. Virological cure did not favor any intervention: OR 0.96, 95% CI 0.54 to 1.7 (p = 0.90), I2 = 58%. Seroconversion of HBsAg to negative favored placebo/standard-of-care compared to lamivudine: OR 0.54, 95% CI 0.33 to 0.9 (p = 0.02), I2 = 31%. The only trial that compared entecavir and lamivudine favored entecavir over lamivudine (OR: 3.64, 95% CI 1.31-10.13; 90 participants). Adverse events were mild. CONCLUSION: There is insufficient evidence that NA obtain superior efficacy compared with placebo/standard-of-care in patients with acute viral hepatitis, based on low quality evidence.

Effects of playing 1 vs 3 matches in a one-week period on physical performance in young soccer players.

The aim of this study was to analyse the effects of playing 1 vs 3 matches in a one-week period on physical performance in young soccer players. Twelve youth soccer players completed a battery of physical tests (countermovement jump [CMJ], 25 m sprint, 5-0-5 agility test, ankle dorsiflexion range of motion [AD ROM]) 72 h after a match. These tests were performed on two different occasions: during a week with 1 competitive match, and during a week in which 3 matches were played. Three matches in a week caused from most likely to very likely impairments in CMJ (ES = 0.81), the 5-0-5 agility test (ES = 1.03), and in AD ROM (ES = 0.46-0.63) compared with the 1 match in a week. For the 25 m sprint test, performance impairments were found in the split times for 10-15 m (ES = 0.72), 15-20 m (ES = 0.52) and 20-25 m (ES = 0.90) compared with 1 match in a week. Jumping, sprinting, change of direction (COD) performance and AD ROM are significantly affected during congested calendars in young soccer players. The monitoring of these variables is a useful tool to assess players' recovery and may help in determining players' readiness for the next matches.

New susceptibility loci for severe COVID-19 by detailed GWAS analysis in European populations

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic [~]0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.

COMBINATION OF TOCILIZUMAB AND STEROIDS TO IMPROVE MORTALITY IN PATIENTS WITH SEVERE COVID-19 INFECTION: A SPANISH, MULTICENTER, COHORT STUDY

BackgroundWe aimed to determine the impact of tocilizumab use in severe COVID-19 pneumonia mortality. MethodsWe performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain, from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by Inverse Probability of the Treatment Weights (IPTW). Tocilizumab effect in patients receiving steroids during the 48h following inclusion was analyzed. ResultsDuring the study period, 506 patients with severe COVID-19 fulfilled inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days (IQR 8-14). Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls (16.8% versus 31.5%, HR 0.514 [95CI 0.355-0.744], p< 0.001; weighted HR 0.741 [95CI 0.619-0.887], p = 0.001). Tocilizumab treatment reduced mortality by 14.7% relative to no tocilizumab treatment (RRR 46.7%). We calculated a number necessary to treat of 7. Among patients treated with steroids, mortality was lower in patients treated with tocilizumab than in those treated with steroids alone (10.9% versus 40.2%, HR 0.511 [95CI 0.352-0.741], p = 0.036; weighted HR 0.6 [95CI 0.449-0.804], p< 0.001) (Interaction p = 0.094). ConclusionsThese results show that survival of patients with severe COVID-19 is higher in patients treated with tocilizumab than in those not treated, and that tocilizumab effect adds to that of steroids administered to non-intubated cases with COVID-19 during the first 48 hours of presenting with respiratory failure despite of oxygen therapy. Randomised controlled studies are needed to confirm these results. SummaryWe investigated in-hospital mortality of patients with severe SARS-CoV-2 pneumonia in a multicenter series of patients treated with tocilizumab compared to controls, and adjusted using IPTW. Our results show a beneficial impact of tocilizumab treatment in SARS-CoV-2 pneumonia, that adds to that of steroids.

Bacterial natural transformation by highly fragmented and damaged DNA.

DNA molecules are continuously released through decomposition of organic matter and are ubiquitous in most environments. Such DNA becomes fragmented and damaged (often <100 bp) and may persist in the environment for more than half a million years. Fragmented DNA is recognized as nutrient source for microbes, but not as potential substrate for bacterial evolution. Here, we show that fragmented DNA molecules (≥ 20 bp) that additionally may contain abasic sites, cross-links, or miscoding lesions are acquired by the environmental bacterium Acinetobacter baylyi through natural transformation. With uptake of DNA from a 43,000-y-old woolly mammoth bone, we further demonstrate that such natural transformation events include ancient DNA molecules. We find that the DNA recombination is RecA recombinase independent and is directly linked to DNA replication. We show that the adjacent nucleotide variations generated by uptake of short DNA fragments escape mismatch repair. Moreover, double-nucleotide polymorphisms appear more common among genomes of transformable than nontransformable bacteria. Our findings reveal that short and damaged, including truly ancient, DNA molecules, which are present in large quantities in the environment, can be acquired by bacteria through natural transformation. Our findings open for the possibility that natural genetic exchange can occur with DNA up to several hundreds of thousands years old.

Upregulation of trefoil factor 3 (TFF3) after rectal cancer chemoradiotherapy is an adverse prognostic factor and a potential therapeutic target.

PURPOSE: Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance. METHODS: This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival. RESULTS: Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis. CONCLUSION: Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target.

A combined strategy of SAGE and quantitative PCR Provides a 13-gene signature that predicts preoperative chemoradiotherapy response and outcome in rectal cancer.

PURPOSE: Preoperative chemoradiotherapy (CRT) is the treatment of choice for rectal cancer (RC), but half of the patients do not respond, suffer unnecessary toxicities, and surgery delays. We aimed to develop a model that could predict a clinically meaningful response to CRT by using formalin-fixed paraffin-embedded (FFPE) biopsies. EXPERIMENTAL DESIGN: We first carried out an exploratory screening of candidate genes by using SAGE technology to evaluate dynamic changes in the RC transcriptome in selected refractory patients before and after CRT. Next, 53 genes (24 from SAGE and 29 from the literature) were analyzed by qPCR arrays in FFPE initial biopsies from 94 stage II/III RC patients who were preoperatively treated with CRT. Tumor response was defined by using Dworak's tumor regression grade (2-3-4 vs. 0-1). Multivariate Cox methods and stepwise algorithms were applied to generate an optimized predictor of response and outcome. RESULTS: In the training cohort (57 patients), a 13-gene signature predicted tumor response with 86% accuracy, 87% sensitivity, and 82% specificity. In a testing cohort (37 patients), the model correctly classified 6 of 7 nonresponders, with an overall accuracy of 76%. A signature-based score identified patients with a higher risk of relapse in univariate (3-year disease-free survival 64% vs. 90%, P = 0.001) and multivariate analysis (HR = 4.35 95% CI: 1.2-15.75, P = 0.02), in which it remained the only statistically significant prognostic factor. CONCLUSIONS: A basal 13-gene signature efficiently predicted CRT response and outcome. Multicentric validation by the GEMCAD collaborative group is currently ongoing. If confirmed, the predictor could be used to improve patient selection in RC studies.

Parallel anticancer drug development and molecular stratification to qualify predictive biomarkers: dealing with obstacles hindering progress.

Current anticancer drug development still largely follows the classic designs developed for chemotherapeutic agents over the past 4 to 5 decades, remaining slow, costly, and inefficient, with continuing high risks of costly late drug attrition. A Pharmacologic Audit Trail has been described to decrease these risks, incorporating pharmacokinetic, pharmacodynamic, intermediate efficacy endpoints, as well as patient stratification molecular biomarkers. Molecular biomarker-based patient selection in hypothesis-testing early clinical trials is critical to clinically qualify putative predictive biomarkers for rationally designed, molecularly targeted drugs as early as possible. Nevertheless, major concerns have been raised about the impact of using such biomarkers in early trials, in view of the costs and time involved to develop multiple certified assays for clinical use. The rapid evolution of novel technologies of utility to this field, such as next-generation sequencing and circulating tumor-cell isolation, makes these valid concerns of critical importance. We therefore propose a more efficient parallel predictive biomarker and clinical anticancer drug development process to deal with the obstacles hindering progress.