Diagnostic performance of FibroTest, SteatoTest and ActiTest in patients with NAFLD using the SAF score as histological reference

BACKGROUND: Blood tests of liver injury are less well validated in non‐alcoholic fatty liver disease (NAFLD) than in patients with chronic viral hepatitis. AIMS: To improve the validation of three blood tests used in NAFLD patients, FibroTest for fibrosis staging, SteatoTest for steatosis grading and ActiTest for inflammation activity grading. METHODS: We pre‐included new NAFLD patients with biopsy and blood tests from a single‐centre cohort (FibroFrance) and from the multicentre FLIP consortium. Contemporaneous biopsies were blindly assessed using the new steatosis, activity and fibrosis (SAF) score, which provides a reliable and reproducible diagnosis and grading/staging of the three elementary features of NAFLD (steatosis, inflammatory activity) and fibrosis with reduced interobserver variability. We used nonbinary‐ROC (NonBinAUROC) as the main endpoint to prevent spectrum effect and multiple testing. RESULTS: A total of 600 patients with reliable tests and biopsies were included. The mean NonBinAUROCs (95% CI) of tests were all significant (P < 0.0001): 0.878 (0.864–0.892) for FibroTest and fibrosis stages, 0.846 (0.830–0.862) for ActiTest and activity grades, and 0.822 (0.804–0.840) for SteatoTest and steatosis grades. FibroTest had a higher NonBinAUROC than BARD (0.836; 0.820–0.852; P = 0.0001), FIB4 (0.845; 0.829–0.861; P = 0.007) but not significantly different than the NAFLD score (0.866; 0.850–0.882; P = 0.26). FibroTest had a significant difference in median values between adjacent stage F2 and stage F1 contrarily to BARD, FIB4 and NAFLD scores (Bonferroni test P < 0.05). CONCLUSIONS: In patients with NAFLD, SteatoTest, ActiTest and FibroTest are non‐invasive tests that offer an alternative to biopsy, and they correlate with the simple grading/staging of the SAF scoring system across the three elementary features of NAFLD: steatosis, inflammatory activity and fibrosis

Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk

Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism

Three-dimensional time and frequency-domain theory of femtosecond x-ray pulse generation through Thomson scattering

The generation of high intensity, ultrashort x-ray pulses enables exciting new experimental capabilities, such as femtosecond pump-probe experiments used to temporally resolve material structural dynamics on atomic time scales. Thomson backscattering of a high intensity laser pulse with a bright relativistic electron bunch is a promising method for producing such high-brightness x-ray pulses in the 10–100 keV range within a compact facility. While a variety of methods for producing subpicosecond x-ray bursts by Thomson scattering exist, including compression of the electron bunch to subpicosecond bunch lengths and/or colliding a subpicosecond laser pulse in a side-on geometry to minimize the interaction time, a promising alternative approach to achieving this goal while maintaining ultrahigh brightness is the production of a time-correlated (or chirped) x-ray pulse in conjunction with pulse slicing or compression. We present the results of a complete analysis of this process using a recently developed 3D time and frequency-domain code for analyzing the spatial, temporal, and spectral properties an x-ray beam produced by relativistic Thomson scattering. Based on the relativistic differential cross section, this code has the capability to calculate time and space dependent spectra of the x-ray photons produced from linear Thomson scattering for both bandwidth-limited and chirped incident laser pulses. Spectral broadening of the scattered x-ray pulse resulting from the incident laser bandwidth, laser focus, and the transverse and longitudinal phase space of the electron beam were examined. Simulations of chirped x-ray pulse production using both a chirped electron beam and a chirped laser pulse are presented. Required electron beam and laser parameters are summarized by investigating the effects of beam emittance, energy spread, and laser bandwidth on the scattered x-ray spectrum. It is shown that sufficient temporal correlation in the scattered x-ray spectrum to produce sub-100 fs temporal slice resolution can be produced from state-of-the-art, high-brightness electron beams without the need to perform longitudinal compression on the electron bunch

Three-dimensional time and frequency-domain theory of femtosecond x-ray pulse generation through Thomson scattering

The generation of high intensity, ultrashort x-ray pulses enables exciting new experimental capabilities, such as femtosecond pump-probe experiments used to temporally resolve material structural dynamics on atomic time scales. Thomson backscattering of a high intensity laser pulse with a bright relativistic electron bunch is a promising method for producing such high-brightness x-ray pulses in the 10–100 keV range within a compact facility. While a variety of methods for producing subpicosecond x-ray bursts by Thomson scattering exist, including compression of the electron bunch to subpicosecond bunch lengths and/or colliding a subpicosecond laser pulse in a side-on geometry to minimize the interaction time, a promising alternative approach to achieving this goal while maintaining ultrahigh brightness is the production of a time-correlated (or chirped) x-ray pulse in conjunction with pulse slicing or compression. We present the results of a complete analysis of this process using a recently developed 3D time and frequency-domain code for analyzing the spatial, temporal, and spectral properties an x-ray beam produced by relativistic Thomson scattering. Based on the relativistic differential cross section, this code has the capability to calculate time and space dependent spectra of the x-ray photons produced from linear Thomson scattering for both bandwidth-limited and chirped incident laser pulses. Spectral broadening of the scattered x-ray pulse resulting from the incident laser bandwidth, laser focus, and the transverse and longitudinal phase space of the electron beam were examined. Simulations of chirped x-ray pulse production using both a chirped electron beam and a chirped laser pulse are presented. Required electron beam and laser parameters are summarized by investigating the effects of beam emittance, energy spread, and laser bandwidth on the scattered x-ray spectrum. It is shown that sufficient temporal correlation in the scattered x-ray spectrum to produce sub-100 fs temporal slice resolution can be produced from state-of-the-art, high-brightness electron beams without the need to perform longitudinal compression on the electron bunch