Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

BackgroundHistologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD.MethodsThis was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0–4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0–2 vs F3 vs F4; LSM: 2·67; NFS: 0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226.FindingsOf 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44–63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33–91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62–0·81) for histology, 0·76 (0·70–0·83) for LSM-VCTE, 0·74 (0·64–0·82) for FIB-4, and 0·70 (0·63–0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression.InterpretationSimple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Nonalcoholic Fatty Liver Disease: Modulating Gut Microbiota to Improve Severity?

International audienceGut microbiota plays a role in the pathophysiology of metabolic diseases which also include nonalcoholic fatty liver diseases (NAFLD), through the gut-liver axis. To date, clinical guidelines recommend a weight loss goal of 7 to 10% to improve features of NAFLD. Nevertheless, since this target is not easily achieved by all patients, alternative therapeutic options are currently being evaluated. This review focusses on therapeutics that aims to modulate the gut microbiota and the gut-liver axis. We will herein discuss how probiotics, prebiotics, synbiotic, fecal microbiota transfer, polyphenols, specific diets and exercise interventions have been shown to modify gut microbiota signatures, improve NAFLD outcomes and detail, when available, the different mechanisms by which these beneficial outcomes might occur. Apart from probiotics which have already been tested in human RCTs, most of these potential therapeutics have been studied in animals. Their efficacy still warrants confirmation in humans using appropriate design

Metabolism and Metabolic Disorders and the Microbiome: The Intestinal Microbiota Associated With Obesity, Lipid Metabolism, and Metabolic Health—Pathophysiology and Therapeutic Strategies: The Intestinal Microbiota Associated With Obesity, Lipid Metabolism, and Metabolic Health: Pathophysiology and Therapeutic Strategies

Changes in the intestinal microbiome have been associated with obesity and type 2 diabetes, in epidemiological studies and studies of the effects of fecal transfer in germ-free mice. We review the mechanisms by which alterations in the intestinal microbiome contribute to development of metabolic diseases, and recent advances, such as the effects of the microbiome on lipid metabolism. Strategies have been developed to modify the intestinal microbiome and reverse metabolic alterations, which might be used as therapies. We discuss approaches that have shown effects in mouse models of obesity and metabolic disorders, and how these might be translated to humans to improve metabolic health

Density Enhancement of RRAMs using a RESET Write Termination for MLC Operation

International audienceThis article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC B

ProximiTEE: Hardened SGX Attestation by Proximity Verification

Intel SGX enables protected enclaves on untrusted computing platforms. An important part of SGX is its remote attestation mechanism that allows a remote verifier to check that the expected enclave was correctly initialized before provisioning secrets to it. However, SGX attestation is vulnerable to relay attacks where the attacker, using malicious software on the target platform, redirects the attestation and therefore the provisioning of confidential data to a platform that he physically controls. Although relay attacks have been known for a long time, their consequences have not been carefully examined. In this paper, we analyze relay attacks and show that redirection increases the adversary's abilities to compromise the enclave in several ways, enabling for instance physical and digital side-channel attacks that would not be otherwise possible. We propose ProximiTEE, a novel solution to prevent relay attacks. Our solution is based on a trusted embedded device that is attached to the target platform. Our device verifies the proximity of the attested enclave, thus allowing attestation to the intended enclave regardless of malicious software, such as a compromised OS, on the target platform. The device also performs periodic proximity verification which enables secure enclave revocation by detaching the device. Although proximity verification has been proposed as a defense against relay attacks before, this paper is the first to experimentally demonstrate that it can be secure and reliable for TEEs like SGX. Additionally, we consider a stronger adversary that has obtained leaked SGX attestation keys and emulates an enclave on the target platform. To address such emulation attacks, we propose a second solution where the target platform is securely initialized by booting it from the attached embedded device

Globale Gesundheit: Lehrbuch für den Öffentlichen Gesundheitsdienst

Dogan Ö, Gepp S, Hommes F, et al. Globale Gesundheit: Lehrbuch für den Öffentlichen Gesundheitsdienst. 1st ed. Düsseldorf: Akademie für Öffentliches Gesundheitswesen; 2020

Sex-related differences in patients at high bleeding risk undergoing percutaneous coronary intervention: a patient-level Pooled analysis from 4 postapproval studies

Background Women have been associated with higher rates of recurrent events after percutaneous coronary intervention than men, possibly attributable to advanced age at presentation and greater comorbidities. These factors also put women at higher risk of bleeding, which may influence therapeutic strategies and clinical outcomes. Methods and Results We performed a patient-level pooled analysis of 4 postapproval registries to evaluate sex-related differences in patients at high bleeding risk (HBR) undergoing percutaneous coronary intervention. HBR required fulfillment of at least 1 major or 2 minor criteria of the Academic Research Consortium definition. Outcomes of interest were major bleeding and major adverse cardiac events (composite of cardiac death, myocardial infarction, or definite/probable stent thrombosis). Of the total 10 502 patients, 2832 (27.0%) were women. The prevalence of HBR was higher in women compared with men (29.0% versus 20.5%, P<0.0001). Women at HBR were older and had more comorbidities, while men at HBR were more often smokers, with prior myocardial infarction and more complex coronary lesions. At 4 years, women at HBR had significantly higher major bleeding compared with men at HBR (10.8% versus 6.2%, P<0.0001); however, this difference was attenuated after multivariable adjustment (hazard ratio, 0.92; 95% CI, 0.41-2.08). Major adverse cardiac event rates between groups were similar (12.2% versus 12.6%, P=0.82) and remained consistent after adjustment (hazard ratio, 0.64; 95% CI, 0.32-1.28). Conclusions The prevalence of HBR was higher in women compared with men, with considerable differences in the distribution of criteria. Women at HBR experienced higher rates of major bleeding but similar major adverse cardiac event rates compared with men at HBR at 4 years

Oak stands along an elevation gradient have different molecular strategies for regulating bud phenology

International audienceBackground Global warming raises serious concerns about the persistence of species and populations locally adapted to their environment, simply because of the shift it produces in their adaptive landscape. For instance, the phenological cycle of tree species may be strongly affected by higher winter temperatures and late frost in spring. Given the variety of ecosystem services they provide, the question of forest tree adaptation has received increasing attention in the scientific community and catalyzed research efforts in ecology, evolutionary biology and functional genomics to study their adaptive capacity to respond to such perturbations. Results In the present study, we used an elevation gradient in the Pyrenees Mountains to explore the gene expression network underlying dormancy regulation in natural populations of sessile oak stands sampled along an elevation cline and potentially adapted to different climatic conditions mainly driven by temperature. By performing analyses of gene expression in terminal buds we identified genes displaying significant dormancy, elevation or dormancy-byelevation interaction effects. Our Results highlighted that low-and high-altitude populations have evolved different molecular strategies for minimizing late frost damage and maximizing the growth period, thereby increasing potentially their respective fitness in these contrasting environmental conditions. More particularly, population from high elevation overexpressed genes involved in the inhibition of cell elongation and delaying flowering time while genes involved in cell division and flowering, enabling buds to flush earlier were identified in population from low elevation. Conclusion Our study made it possible to identify key dormancy-by-elevation responsive genes revealing that the stands analyzed in this study have evolved distinct molecular strategies to adapt their bud phenology in response to temperature

Benefits of Iterative Searches of Large Databases to Interpret Large Human Gut Metaproteomic Data Sets

International audienc