Therapeutic drug monitoring to improve outcome of anti-TNF drugs in pediatric inflammatory bowel disease

Introduction: Medical treatment of pediatric inflammatory bowel diseases (IBD) has been greatly changed by the introduction of a number of biologic agents that are able to target various players of the immune response. In particular, monoclonal antibodies against the pro-inflammatory cytokine TNF-alpha (TNF) such as infliximab, adalimumab, and golimumab are now in the clinics both in induction and maintenance therapy, and several efforts are currently ongoing to optimize the use of these drugs in children. Areas covered: This review focuses on therapeutic drug monitoring (TDM) of anti-TNF levels and antidrug antibodies (ADAs), in IBD children. A revision of the analytical assays used for assessing anti-TNF plasma levels is also provided. Expert opinion: Although there is a consensus across studies that higher anti-TNF trough levels are associated with a better clinical outcome, and that early anti-TNF serum measurements could be predictive of long-term response, it is still not clear what the best predictive time of sampling is and what the ideal target drug plasma concentration to achieve. Indeed, there are a number of published studies, particularly in pediatric cohorts, limited by the population size analyzed and more prospective large studies are needed to examine the value of these predictive markers

Comparison of accuracy of single crowns generated from digital and conventional impressions: An in vivo controlled trial

Aim With the advances of digital technology, intraoral digital impression (DI) technique has become a major trend in prosthodontics with respect to traditional impression (TI) techniques; despite that, very few data are available concerning its accuracy. Thus, the purpose of this study was to compare the effectiveness of DI versus TI considering both marginal and internal gap (MG, IG, respectively) in cobalt-chromium (Co-Cr) single crowns manufactured by mean of computer-aided design and computer-aided manufacturing (CAD/CAM) technology. Material and methods Thirty posterior teeth were considered for this study. For each abutment tooth, sixty and thirty copings were produced with the aid of TI and DI, respectively. Thirty of the sixty copings of the TI-group were then randomly selected to be veneered and cemented onto existing abutments. The space existing between the internal surface of the coping and the abutment tooth was evaluated onto an in vitro replica; the MG and IG were measured by Scanning Electron Microscope. The data were analysed by the Wilcoxon test (1-tailed). Results The mean MG was 75.04 μm (SD = 13.12) and 55.01 μm (SD = 7.01) for the TI group and DI group, respectively. As regards the mean IGs, the values recorded were of 78.36 μm (SD = 19.66) for the TI-group and 59.20 μm (SD=3.33) for the DI-group. A statistically significant difference was found between the two groups (p-value = 0.001). Conclusions Copings manufactured from DI showed better MGs and IGs with respect to copings produced from TI. However, both approaches produced clinically acceptable results

Covid-19 vaccine: A survey of hesitancy in patients with celiac disease

(1) Background: COVID-19 vaccination campaigns offer the best hope of controlling the pandemic. However, the fast production of COVID-19 vaccines has caused concern among the general public regarding their safety and efficacy. In particular, patients with chronic illnesses, such as celiac disease (CD), may be more fearful. Information on vaccine hesitancy plays a pivotal role in the development of an efficient vaccination campaign. In our study, we aimed to evaluate COVID-19 vaccine hesitancy among Italian CD patients. (2) Methods: an anonymous questionnaire was sent to CD patients followed at our tertiary referral center for CD in Milan, Italy. Patients were defined as willing, hesitant and refusing. We evaluated the reasons for hesitancy/refusal and the possible determinants, calculating crude and adjusted odds ratios [AdjORs] with 95% confidence intervals [CIs]. (3) Results: the questionnaire was sent to 346 patients with a response rate of 29.8%. Twenty-six (25.2%) of the 103 respondents were hesitant, with a total refusal rate of 4.8%. The main reason was fear of adverse events related to vaccination (68.2%). Among hesitant patients, 23% declared that their opinion was influenced by their CD. The determinants positively influencing willingness to be vaccinated against COVID-19 were adherence to a GFD, perception of good knowledge about COVID-19 and its vaccines, and a positive attitude to previous vaccines (AdjOR 12.71, 95% CI 1.82–88.58, AdjOR 6.50, 95% CI 1.44–29.22, AdjOR 0.70, 95% CI 0.11–4.34, respectively). (4) Conclusions: CD patients should be vaccinated against COVID-19 and a specific campaign to address the determinants of hesitancy should be developed

Proceedings of the Workshop on Monte Carlo's, Physics and Simulations at the LHC PART II

These proceedings collect the presentations given at the first three meetings of the INFN "Workshop on Monte Carlo's, Physics and Simulations at the LHC", held at the Frascati National Laboratories in 2006. The first part of these proceedings contains pedagogical introductions to several basic topics of both theoretical and experimental high pT LHC physics. The second part collects more specialised presentations.Comment: 157 pages, 136 figures; contribution by M. Grazzini has been adde

Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants

The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Candidate genetic variants (TPMT rs1142345, rs1800460, rs1800462, GSTA1 rs3957357, GSTM1, and GSTT1 deletion) were determined by polymerase chain reaction (PCR) assays and pyrosequencing. Statistical analysis was performed using linear mixed effects models for the association between the candidate variants and the pharmacological variables (azathioprine doses and metabolites). Azathioprine metabolites were measured in 257 samples (median 2 per patient, inter-quartile range IQR 1-3). Clinical efficacy at the first evaluation available resulted better in ulcerative colitis than in Crohn's disease patients (88.0% versus 52.5% responders, p = 0.0003, linear mixed effect model, LME). TGN concentration and the ratio TGN/dose at the first evaluation were significantly higher in responder. TPMT rs1142345 variant (4.8% of patients) was associated with increased TGN (LME p = 0.0042), TGN/dose ratio (LME p < 0.0001), decreased azathioprine dose (LME p = 0.0087), and MMPN (LME p = 0.0011). GSTM1 deletion (58.1% of patients) was associated with a 18.5% decrease in TGN/dose ratio and 30% decrease in clinical efficacy. GSTA1 variant (12.8% of patients) showed a trend (p = 0.049, LME) for an association with decreased clinical efficacy; however, no significant effect on azathioprine pharmacokinetics could be detected. In conclusion, GSTs variants are associated with azathioprine efficacy and pharmacokinetics

Summary of the fourth international workshop on deep learning for testing and testing for deep learning (DeepTest 2023)

Deep Learning (DL) techniques help software developers thanks to their ability to learn from historical information which is useful in several program analysis and testing tasks (e.g., malware detection, fuzz testing, bug-finding, and type-checking). DL-based software systems are also increasingly adopted in safety-critical domains, such as autonomous driving, medical diagnosis, and aircraft collision avoidance systems. In particular, testing the correctness and reliability of DL-based systems is paramount, since a failure of such systems would cause a significant safety risk for the involved people and/or environment. The 4th International Workshop on Deep Learning for Testing and Testing for Deep Learning (DeepTest 2023) was co-located with the 45th International Conference on Software Engineering (ICSE), with the goal of targeting research at the intersection of software engineering and deep learning and devise novel approaches and tools to ensure the interpretability and dependability of software systems that depends on DL components

Long non-coding RNA gas5 and intestinal mmp2 and mmp9 expression: A translational study in pediatric patients with IBD

Background: The long non-coding RNA (lncRNA) growth arrest–specific transcript 5 (GAS5) seems to be involved in the regulation of mediators of tissue injury, in particular matrix metalloproteinases (MMPs), implicated in the pathogenesis of inflammatory bowel disease (IBD). We investigated the role of GAS5 in regulating MMP2 and MMP9 expression in pediatric patients with IBD and in vitro. Methods: In total, 25 IBD patients were enrolled: For each patient paired inflamed and non-inflamed biopsies were collected. RNA was extracted and GAS5, MMP2, and MMP9 were quantified by TaqMan assay. The expression of GAS5 and MMPs was also determined in the human monocytic THP1 cells differentiated into macrophages and stimulated with lipopolysaccharide (LPS). The function of GAS5 was assessed by overexpressing the lncRNA and evaluating the MMPs levels. Results: Real-time PCR results demonstrated a downregulation of GAS5 and an upregulation of both MMPs in inflamed tissues. In vitro data confirmed the trend observed in patients for the three genes: The stimulation with LPS promoted a downregulation of GAS5 while an increase of MMPs was observed. Overexpression experiments showed that higher levels of GAS5 lead to a decrease of both enzymes. Conclusion: These results provide new information about the role of GAS5 in IBD: The lncRNA could mediate tissue damage by modulating the expression of MMPs