A non-invasive algorithm accurately predicts advanced fibrosis in hepatitis C: a comparison using histology with internal-external validation

BACKGROUND/AIMS: Biochemical tests and ultrasonography (US) are useful in the non-invasive assessment of liver fibrosis in patients with chronic hepatitis C (CH-C); however histology remains the reference standard. This multicenter, cross-sectional cohort study evaluated the accuracy of APRI (AST-to-platelet-ratio-index) and liver surface ultrasound nodularity (LSN), singularly and sequentially combined in an algorithm, in diagnosing advanced fibrosis (i.e. METAVIR F3,F4), to derive a prediction rule to confirm or exclude F3,F4. METHODS: Four hundred and thirty consecutive CH-C patients with elevated ALT, grouped into a first cohort (training set), and an internal and an external validation cohort, were studied. APRI and LSN were compared to liver biopsy and sequentially combined in order to obtain a predictive rule for advanced fibrosis METAVIR F3,F4. RESULTS: LSN was negative and APRI1 in 185/430 patients, whereas LSN was positive and APRI>2 in 46/430 cases, with a 94% diagnostic accuracy for presence/absence of F3, F4, respectively. In a further 60/430 patients, F3,F4 was detected with an accuracy of 83%. In the remaining cases no classification was possible. CONCLUSIONS: An algorithm based on APRI and LSN confirms or excludes F3,F4 in 54% of CH-C patients with elevated ALT and suggests a highly probable diagnosis in a further one-sixth of patients, thus rendering liver biopsy unnecessary in these patients.     

Emotion in motion: Facial dynamics affect infants' neural processing of emotions

Research investigating the early development of emotional processing has focused mainly on infants' perception of static facial emotional expressions, likely restricting the amount and type of information available to infants. In particular, the question of whether dynamic information in emotional facial expressions modulates infants' neural responses has been rarely investigated. The present study aimed to fill this gap by recording 7-month-olds' event-related potentials to static (Study 1) and dynamic (Study 2) happy, angry, and neutral faces. In Study 1, happy faces evoked a faster right-lateralized negative central (Nc) component compared to angry faces. In Study 2, both happy and angry faces elicited a larger right-lateralized Nc compared to neutral faces. Irrespective of stimulus dynamicity, a larger P400 to angry faces was associated with higher scores on the Negative Affect temperamental dimension. Overall, results suggest that 7-month-olds are sensitive to facial dynamics, which might play a role in shaping the neural processing of facial emotional expressions. Results also suggest that the amount of attentional resources infants allocate to angry expressions is associated to their temperamental traits. These findings represent a promising avenue for future studies exploring the neurobiological processes involved in perceiving emotional expressions using dynamic stimuli.     

Sclerostin Regulation,Microarchitecture, and Advanced Glycation End-Products in the Bone of Elderly Women With Type 2 Diabetes

Increased circulating sclerostin and accumulation of advanced glycation end-products (AGEs) are two potential mechanisms underlying low bone turnover and increased fracture risk in type 2 diabetes (T2D). Whether the expression of the sclerostin-encoding SOST gene is altered in T2D, and whether it is associated with AGEs accumulation or regulation of other bone formation-related genes is unknown. We hypothesized that AGEs accumulate and SOST gene expression is upregulated in bones from subjects with T2D, leading to downregulation of bone forming genes (RUNX2 and osteocalcin) and impaired bone microarchitecture and strength. We obtained bone tissue from femoral heads of 19 T2D postmenopausal women (mean glycated hemoglobin [HbA1c] 6.5%) and 73 age- and BMI-comparable nondiabetic women undergoing hip replacement surgery. Despite similar bone mineral density (BMD) and biomechanical properties, we found a significantly higher SOST (p = .006) and a parallel lower RUNX2 (p = .025) expression in T2D compared with non-diabetic subjects. Osteocalcin gene expression did not differ between T2D and non-diabetic subjects, as well as circulating osteocalcin and sclerostin levels. We found a 1.5-fold increase in total bone AGEs content in T2D compared with non-diabetic women (364.8 ± 78.2 versus 209.9 ± 34.4 μg quinine/g collagen, respectively; p < .001). AGEs bone content correlated with worse bone microarchitecture, including lower volumetric BMD (r = −0.633; p = .02), BV/TV (r = −0.59; p = .033) and increased trabecular separation/spacing (r = 0.624; p = .023). In conclusion, our data show that even in patients with good glycemic control, T2D affects the expression of genes controlling bone formation (SOST and RUNX2). We also found that accumulation of AGEs is associated with impaired bone microarchitecture. We provide novel insights that may help understand the mechanisms underlying bone fragility in T2D. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Heparin-induced thrombocytopenia: detection of antiheparin/PF4 antibodies by means of heparin/PF4-coated beads and flow cytometry

A total of 70 serum samples from heparin-induced thrombocytopenia (HIT II) patients, non-HIT patients and healthy subjects, respectively, were studied for the presence of antiheparin/PF4 antibodies. Two enzyme-linked immunosorbent assay (ELISA) assays were compared with the particle gel immunoassay (PaGIA). Beads of the PaGIA kit were also used to evaluate the feasibility of flow cytometric detection of antiheparin/PF4 antibodies in patient samples. Experiments have shown that all samples found positive by ELISA and PaGIA, were also positive when analysed by flow cytometry by an indirect test using the high-density particles coated with heparin/PF4 complexes and a second step fluorescein isothiocyanate (FITC) antihuman immunoglobulin (Ig)G reagent. The procedure was easy to perform, repetitive and beads were promptly visualized by physical parameters, with a very low background. In conclusion, the results of this study suggest that flow cytometry is a reliable method for the detection of antiheparin/PF4 antibodies.     

In vivo antibacterial effects of simulated human serum profiles of once-daily versus thrice-daily dosing of amikacin in a Serratia marcescens endocarditis experimental model.

Once-daily dosage of aminoglycosides is currently under consideration. The lower toxicity of this regimen has been clearly established, but there are conflicting experimental and clinical data concerning its efficacy. It is inadvisable to optimize human therapy by extrapolation from experimental studies since animal and human pharmacokinetics differ. The simulation of human pharmacokinetics in experimental infectious models would seem to offer a more rational approach. We used computer-controlled infusion of amikacin at a variable flow rate to simulate human pharmacokinetics in a Serratia marcescens rabbit endocarditis model and to compare two therapeutic regimens (once-daily versus thrice-daily doses). The doses corresponded to simulations of 15 and 30 mg/kg of body weight per day in humans, and antibacterial activity was measured in vegetations (Veg) after 24 h of treatment. The results show that the dose corresponding to 15 mg/kg/day failed to produce a significant reduction of CFU (6.8 +/- 0.9 and 6.4 +/- 0.8 log10 CFU/g of Veg, respectively, for once-daily and thrice-daily doses versus 7.6 +/- 1.0 for controls). A significant reduction was observed only for the dose corresponding to 30 mg/kg/day in humans (5.2 +/- 1.5 and 5.4 +/- 1.1 log10 CFU/g of Veg, respectively, for the two regimens). With this model, the efficacy of amikacin was similar for both regimens after 24 h of treatment simulating human pharmacokinetics.     

Primer extension assay for prion protein genotype determination in sheep

Scrapie is a transmissible spongiform encephalopathy (TSE) which affects sheep and goats. TSEs are characterised by the conversion of the cellular prion protein (PrP(C)) into the pathological form PrP(Sc). The occurrence of scrapie in sheep is influenced by polymorphisms in the PrP gene; in particular, three codons (136, 154 and 171) are important in conditioning the susceptibility/resistance of sheep to the disease, with the Val/Val(136) Arg/Arg(154) Gln/Gln(171) genotype being the most susceptible and the Ala/Ala(136) Arg/Arg(154) Arg/Arg(171), the most resistant one. The latter genotype seems to confer, in sheep, resistance to the oral infection with bovine spongiform encephalopathy, as well. The selection of genetically resistant sheep populations represents the basis of the recent strategies against ovine TSE in the European Union (EU). Herein, we describe a rapid and simple method, based on the primer extension technique, for PrP genotype determination at codons 136, 154 and 171. Intra-laboratory validation of the method showed accuracy levels comparable to those of sequencing analysis. Such method could be used for both the application of the EU policies requiring PrP genotype analysis in all ovine TSE cases, and the large-scale genotyping claimed by the implementation of breeding programmes for genetic resistance to TSE in sheep.     

Replacement fluids in plasmapheresis: cross-over comparative study

Objective: To compare the tolerance and the cost of three replacement fluids in plasmapheresis: albumin 4 % alone, albumin 4 % + dextran 40, or albumin 4 % + hydroxyethylstarch 6 %. Design: A one center randomized, cross-over, comparative study designed to explore the tolerance and the colloid oncotic pressure in patients undergoing plasmapheresis. Patients: 225 plasmapheresis procedures were performed in 27 patients. Measurements and results: Hemodynamic tolerance was good in the three treatment groups. Serum protein concentration after plasmapheresis was significantly lower in the albumin + hydroxyethylstarch group, followed by albumin + dextran 40, versus albumin alone. Colloid oncotic pressure before and after exchange was similar in the three groups. Conclusions: The clinical use of 25–30 % of hydroxyethylstarch 6 % or dextran 40 with albumin 4 % was clinically well tolerated and associated with a 12 % decrease of the cost of substitution solutions.