A Bioequivalence Test by the Direct Comparison of Concentration-versus-Time Curves Using Local Polynomial Smoothers

In order to test if two chemically or pharmaceutically equivalent products have the same efficacy and/or toxicity, a bioequivalence (BE) study is conducted. The 80%/125% rule is the most commonly used criteria for BE and states that BE cannot be claimed unless the 90% CIs for the ratio of selected pharmacokinetics (PK) parameters of the tested to the reference drug are within 0.8 to 1.25. Considering that estimates of these PK parameters are derived from the concentration-versus-time curves, a direct comparison between these curves motivates an alternative and more flexible approach to test BE. Here, we propose to frame the BE test in terms of an equivalence of concentration-versus-time curves which are constructed using local polynomial smoother (LPS). A metric is presented to quantify the distance between the curves and its 90% CIs are calculated via bootstrapping. Then, we applied the proposed procedures to data from an animal study and found that BE between a generic drug and its brand name cannot be concluded, which was consistent with the results by applying the 80%/125% rule. However, the proposed procedure has the advantage of testing only on a single metric, instead of all PK parameters

Automated multi-scale computational pathotyping (AMSCP) of inflamed synovial tissue

Rheumatoid arthritis (RA) is a complex immune-mediated inflammatory disorder in which patients suffer from inflammatory-erosive arthritis. Recent advances on histopathology heterogeneity of RA synovial tissue revealed three distinct phenotypes based on cellular composition (pauci-immune, diffuse and lymphoid), suggesting that distinct etiologies warrant specific targeted therapy which motivates a need for cost effective phenotyping tools in preclinical and clinical settings. To this end, we developed an automated multi-scale computational pathotyping (AMSCP) pipeline for both human and mouse synovial tissue with two distinct components that can be leveraged together or independently: (1) segmentation of different tissue types to characterize tissue-level changes, and (2) cell type classification within each tissue compartment that assesses change across disease states. Here, we demonstrate the efficacy, efficiency, and robustness of the AMSCP pipeline as well as the ability to discover novel phenotypes. Taken together, we find AMSCP to be a valuable cost-effective method for both pre-clinical and clinical research

Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments

Machine learning identification of thresholds to discriminate osteoarthritis and rheumatoid arthritis synovial inflammation

Background We sought to identify features that distinguish osteoarthritis (OA) and rheumatoid arthritis (RA) hematoxylin and eosin (H&E)-stained synovial tissue samples. Methods We compared fourteen pathologist-scored histology features and computer vision-quantified cell density (147 OA and 60 RA patients) in H&E-stained synovial tissue samples from total knee replacement (TKR) explants. A random forest model was trained using disease state (OA vs RA) as a classifier and histology features and/or computer vision-quantified cell density as inputs. Results Synovium from OA patients had increased mast cells and fibrosis (p < 0.001), while synovium from RA patients exhibited increased lymphocytic inflammation, lining hyperplasia, neutrophils, detritus, plasma cells, binucleate plasma cells, sub-lining giant cells, fibrin (all p < 0.001), Russell bodies (p = 0.019), and synovial lining giant cells (p = 0.003). Fourteen pathologist-scored features allowed for discrimination between OA and RA, producing a micro-averaged area under the receiver operating curve (micro-AUC) of 0.85±0.06. This discriminatory ability was comparable to that of computer vision cell density alone (micro-AUC = 0.87±0.04). Combining the pathologist scores with the cell density metric improved the discriminatory power of the model (micro-AUC = 0.92±0.06). The optimal cell density threshold to distinguish OA from RA synovium was 3400 cells/mm2, which yielded a sensitivity of 0.82 and specificity of 0.82. Conclusions H&E-stained images of TKR explant synovium can be correctly classified as OA or RA in 82% of samples. Cell density greater than 3400 cells/mm2 and the presence of mast cells and fibrosis are the most important features for making this distinction

Mechanical behaviour of glass fiber weaven UD/high fluidity PA-based polymers for automotive applications

International audienceThis experimental work addresses the mechanical behavior of weaven UD glass fiber-thermoplastic composites designed for layered materials to be used in the automotive industry. The investigation was implemented in terms of the formulation of the PA66-based thermoplastic resins, the architecture of the fibrous reinforcement (warp spacer) and the glass fiber content. Longitudinal and transverse tensile tests results demonstrate the excellent mechanical behavior of these composites, which correlates with the rheological/permeability properties and wettability behaviour. © 2016 Author(s)

Mechanical behaviour of glass fiber weaven UD/high fluidity PA-based polymers for automotive applications

International audienceThis experimental work addresses the mechanical behavior of weaven UD glass fiber-thermoplastic composites designed for layered materials to be used in the automotive industry. The investigation was implemented in terms of the formulation of the PA66-based thermoplastic resins, the architecture of the fibrous reinforcement (warp spacer) and the glass fiber content. Longitudinal and transverse tensile tests results demonstrate the excellent mechanical behavior of these composites, which correlates with the rheological/permeability properties and wettability behaviour. © 2016 Author(s)

Experimental investigation of the mechanical behavior of glass fiber/high fluidity polyamide-based composites for automotive market

International audienceIn this work, we examine the relationships between the microstructure and the mechanical properties of glass fiber–reinforced polyamide 6,6 composite materials ( V f = 54%). These materials made by thermocompression incorporate different grades of high fluidity polyamide-based polymers and two types of quasi-UD glass fiber reinforcement. One is a classic commercial fabric, while the other specially designed and manufactured incorporates weaker tex glass yarns (the spacer) to increase the planar permeability of the preform. The effects of the viscosity of the polymers and their composition on the wettability of the reinforcements were analyzed by scanning electron microscopy observations of the microstructure. The respective influences of the polymers and the spacer on the mechanical performance were determined by uniaxial tensile and compression tests in the directions parallel and transverse to the warp yarns. Not only does the spacer enhance permeability but it also improves physical and mechanical properties: tensile longitudinal Young’s modulus increased from 38.2 GPa to 42.9 GPa (13% growth), tensile strength increased from 618.9 MPa to 697 MPa (3% growth), and decrease in ultimate strain from 1.8% to 1.7% (5% reduction). The correlation of these results with the damage observed post mortem confirms those acquired from analyses of the microstructure of composites and the rheological behaviors of polymers

Additional file 1: of Inflammatory but not apoptotic death of granulocytes citrullinates fibrinogen

Western blot of trans retinoic acid (ATRA)/HL60 at various time points probed with anti-citrullinated histone H3. NO STIM no stimulation, PMA phorbol 12-myristate 13-acetate, IONO ionomycin. (PDF 199 kb