Scientific rationale behind the development and approval of biosimilar infliximab (CT-P13) in Europe

<div><p>Biosimilars are drugs developed to be highly similar to their originator biologic (or ‘reference medicinal product’) with no clinically meaningful differences in purity, efficacy or safety. Production of biologics and biosimilars is highly complex and sensitive, with any change in manufacturing process having a potential impact on efficacy and safety. This review provides an overview of the manufacturing process for these drugs and considers the implications of any process changes. The scientific rationale underlying the regulatory comparability exercise for process-changed reference medicinal products and biosimilars is also discussed, as is the issue of ‘switchability’ from a reference medicinal product to its biosimilar. CT-P13 (Remsima^®, Inflectra^®), a biosimilar of infliximab, is used as a case study to discuss these issues.</p></div

Summary of logistic regression analysis for variables predicting mental health outcomes, controlling for background variables (age, sex, ethnicity, education and drug use).

<p>Note:</p><p>**p<.001,</p><p>*p<.01 Definitive Psychosis was weighted using specific weight designed for this variable; all other variables were weighted using phase one data weights.</p><p>Summary of logistic regression analysis for variables predicting mental health outcomes, controlling for background variables (age, sex, ethnicity, education and drug use).</p

Simple bivariate associations, showing percentages (%) and actual numbers (n) between the index of multiple deprivation (IMD) and mental health outcomes (psychosis, depression, paranoia, auditory-verbal hallucinations (AVHs) and mania).

<p>Simple bivariate associations, showing percentages (%) and actual numbers (n) between the index of multiple deprivation (IMD) and mental health outcomes (psychosis, depression, paranoia, auditory-verbal hallucinations (AVHs) and mania).</p

Data_Sheet_1_Improving spatial predictions of Eucalypt plantation growth by combining interpretable machine learning with the 3-PG model.docx

Accurate predictions of forest plantation growth provide forest managers with improved forest inventory estimates, forest valuation, and timely harvest schedules. Forest process-based models are increasingly used for quantifying current and potential productivity, yield gaps, and factors limiting growth, such as climate variability, soil characteristics, and water deficit. Improvements in the availability and resolution of spatial and temporal data combined with advancements in machine learning algorithms provide new opportunities to improve model predictions. This study shows how interpretable machine learning (ML) can be used to independently predict site soil fertility rating (FR) and incorporate these results into the 3-PG forest process-based model to accurately predict plantation growth. Four ensemble decision tree machine learning models—random forest trees, extremely randomized trees, gradient boost, and XG boost—were trained and compared using spatial cross-validation across the study area. FR predictions were estimated in relation to the influencing soil type and terrain characteristics, and interpretable ML methods were used to show how input feature permutations may relate to the soil fertility predictions. The results show the explanatory variables are similar across the selected ML models, with the strongest influencing variables being water leaching index, site aspect, and the silt and sand soil texture properties. The extremely randomized tree models showed the overall best performance, with only a small variation in performance across the four ML models. The method was applied to Eucalyptus nitens plantations covering over 63,000 ha in north-west Tasmania, Australia. The results using the predicted FR spatial grid with 3-PG show a strong correlation with observed growth for tree diameter and stand volume (R2 tree diameter at breast height = 0.97, RMSE = 0.85 m; R2 stand volume = 0.96, RMSE = 23.1 m3 ha−1) obtained from 161 permanent sample inventory plots ranging from 3 to 31 years old. This method has practical utility for other study sites to calibrate forest plantation soil fertility rating, in both the spatial and point-scale 3-PG model, where spatial data of soil characteristics are available. The derived soil fertility grid can provide valuable insights into the spatial variability of soil fertility in unknown areas.</p

Additional file 1: Figure S1. of Increase in circulating Th17 cells during anti-TNF therapy is associated with ultrasonographic improvement of synovitis in rheumatoid arthritis

Depletion of CD4+ cells attenuates IL-17 responses in the Elispot assay. Cells were stained with CD4-PE pre and post magnetic labelling to assess effectiveness of CD4+ depletion by flow cytometry (A and B). Whole PBMCs prior to depletion contain CD4+ T cells (A) whilst after depletion of CD4+ T cells with magnetic beads, there are virtually no CD4+ T cells present in this representative patient (B). The frequency of IL17-producing peripheral blood mononuclear cells is markedly attenuated when CD4+ cells are depleted from the PBMC population (C). The effects of depletion are shown in three representative patients. PBMC (n = 200,000) prior to and after the depletion from each patient were set up in the IL17 Elispot assay and stimulated with 1 mg/ml anti-CD3 antibody (OKT3 clone). Results are expressed as number of IL17 specific spot forming cells per million PBMC. Representative experimental wells of the IL17 Elispot assay from one patient are shown demonstrating that after depletion of CD4+ cells the number of IL17-positive spots per well is attenuated (D). Each spot represents one cytokine-producing cell. The numbers under each well indicate the total number of IL17-positive spots in that well. spSFC/10 6 specific spot-forming cells per million PBMC. (DOCX 127 kb

Additional file 2: Figure S2. of Increase in circulating Th17 cells during anti-TNF therapy is associated with ultrasonographic improvement of synovitis in rheumatoid arthritis

Higher frequency of Th17 cells at baseline associated with poorer response to anti-TNF treatment. Positive correlations are shown between percentages of circulating CD4 + IL17+ cells (determined by intracellular cytokine staining using flow cytometry) at baseline and the change in quantitative score for synovial vascularity (10 MCP Trans PDA score) from baseline to week 1 on treatment (A) in patients with RA with presence of power Doppler signal at baseline (n = 19). Also positive correlations are shown between the percentages of circulating CD4 + IL17+ cells at baseline and the change in quantitative score for synovial thickening (10 MCP Trans STA score) from baseline to week 1 (B), from baseline to week 4 (C) and from baseline to week 12 (D) on treatment in the whole RA cohort. Correlations was tested using Spearman’s rank method. 10 MCP Trans PDA composite transverse power Doppler area score for synovial vascularity of ten metacarpophalangeal joints, 10 MCP Trans STA composite transverse synovial thickness area score of ten metacarpophalangeal joints. (DOCX 51 kb

Small carnivore ecosystem services data

<div>This file set contains the data analysed in Williams, S.T., Maree, N., Taylor, P., Belmain, S.R., Keith, M. and Swanepoel, L.H. (2017) Predation by small mammalian carnivores in rural agro-ecosystems: An undervalued ecosystem service? Ecosystem Services. doi: 10.1016/j.ecoser.2017.12.006<br></div><div><br></div><div>There are two types of data included:</div><div>1. data from a camera trap survey of small carnivores in a rural agro-ecosystem South Africa. </div><div>2. data from a questionnaire survey of perceptions of small carnivores and the potential ecosystems services they could provide. </div><div><br></div><div>Both raw and processed data are included, along with an R script is also included, showing how we analysed the camera trap data. Please see the article for further details. Please contact Sam Williams ([email protected]) or Lourens Swanepoel ([email protected]) if you have any questions. </div><div><br></div><div>The files provided in this file set are as follows:</div><div><br></div><div>## Camera trap data </div><div><br></div><div>- Raw Camtrap data.csv</div><div>The raw data from the camera traps.</div><div><br></div><div>- CameraTraps.xls</div><div>Contains attributes of camera trap sites used for the camera trap survey.</div><div><br></div><div>- The following processed dat were used in the occupancy analysis</div><div>- SpData.txt</div><div>- box1.txt</div><div>- species names.csv</div><div>- LUTdetailed.shp (land use shapefile used for plotting maps) </div><div><br></div><div>- analysis code.R</div><div>R code used to analyse camera trap data</div><div><br></div><div><br></div><div>## Questionnaire data</div><div><br></div><div>- questionRaw.csv</div><div>All questionnaire data in a raw form</div><div><br></div><div>A graphical abstract is also included.</div

Camera trap locations

Attributes of camera trap locations used in Williams, S.T., Maree, N., Taylor, P., Belmain, S.R., Keith, M. and Swanepoel, L.H. (in review) Predation by small mammalian carnivores in rural agro-ecosystems: An undervalued ecosystem service? Ecosystem Services

Additional file 1: Figure S1. of Predicting malignancy in thyroid nodules: feasibility of a predictive model integrating clinical, biochemical, and ultrasound characteristics

Area under the curve for model predicting malignancy. Area under ROC curve = 0.7667 (PDF 14 kb

Representative immunofluorescence staining images of cytospin slides of healthy peripheral blood M1 and M2 MDM.

<p>Immunofluorescence staining of cytospin slides of healthy peripheral blood MDM with the nuclear stain POPO-1 (to confirm presence of cells), TSPO, the macrophage marker CD68 and merging of the three stains. <b>(A)</b> staining of MDM stimulated with LPS plus IFN<i>-</i>γ for 24 hours; <b>(B)</b> staining of MDM stimulated with IL-4 for 24 hours. x400 magnification. Scale bar = 20μm.</p