Current knowledge, challenges and innovations in developmental pharmacology: A combined conect4children Expert Group and European Society for Developmental, Perinatal and Paediatric Pharmacology White Paper

Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion (ADME) throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behavior in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease- and/or target organ-specific examples. Identifying and testing PD targets and effects in special populations, and application of age- and/or population-specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques like preclinical models to study therapeutic strategies, and shift from sequential enrollment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD-related as well as drug safety-related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development

Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study

The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired β cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments

Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study

Objective We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). Research Design and Methods 732 recently diagnosed T2D patients from the IMI-DIRECT study were extensively phenotyped over three years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS) and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. Results Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS, and increasing CLIm; visceral or liver fat, HDL-cholesterol and triglycerides had further independent, though weaker, roles (R2=0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from AUROC=0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS and CLIm was relatively stable (odds ratios 0.07 to 0.09). T2D polygenic risk score and baseline pancreatic fat, GLP-1, glucagon, diet, and physical activity did not show an independent role. Conclusions Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of T2D patients in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression

Cure Kinetics of Hexcel W3T282-42/F155 Graphite/Epoxy Prepreg

NRC publication: Ye

Prevalence and antimicrobial resistance pattern of multidrug-resistant enterococci isolated from clinical specimens

Purpose: Vancomycin-resistant enterococci (VRE) pose an emerging problem in hospitals worldwide. The present study was undertaken to determine the occurrence, species prevalence, antibacterial resistance, and phenotypic and genetic characteristics of VRE isolated in Riyadh hospitals, KSA. Materials and Methods: Two hundred and six isolates of enterococcal species were obtained from clinical samples. The antibiotic susceptibility of isolates and minimum inhibitory concentration (MIC) tests for vancomycin and teicoplanin were determined. Molecular typing of VRE isolates was carried out by using pulsed field gel electrophoresis (PFGE) and the resistance genotype was determined by polymerase chain reaction (PCR). Results: VRE accounted for 3.9% of the isolates and were detected mostly in urine, wound and blood specimens isolated from ICU, internal medicine and surgical wards. All strains were identified to species level and were found to consist of E. faecalis (69.2%), E. faecium (11.3%), E. avium (2.1%), E. hirae (0.8%), E. casseliflavus (1.3%) and E. gallinarum (1.3%) species. According to the susceptibility data obtained, 8 (3.9%) out of 206 isolates were found to be VRE (MICs > 32 μg/ml). The vanA, vanB and vanC gene fragments of E. faecalis, E. faecium and E. gallinarum were amplified from isolates and were detected. PFGE patterns of the VRE isolates revealed homogenous patterns with dominant clone suggesting that the strains intrinsic resistance is independent. Conclusions: This study shows an emergence of VRE along with increased rate of multidrug-resistant enterococci in the area of the study. Regular surveillance of antimicrobial susceptibilities should be done regularly and the risk factors should be determined

Self-fulfilling prophecies of the European <i>knowledge-based bio-economy</i>: the discursive shaping of institutional and policy frameworks in the bio-pharmaceuticals sector

Discourses matter. They help to shape institutions and policies. A new discourse has emerged in recent EU innovation policy centred on the idea of a knowledge-based bio-economy (KBBE). It is officially defined as ‘the sustainable, eco-efficient transformation of renewable biological resources into health, food, energy and other industrial products.’ The KBBE agenda links current problem diagnoses, research priorities, technological innovation, and societal benefits. In analysing the KBBE discourse, this paper draws on the sociology of technological expectations, which emphasises the performative, mobilising and self-fulfilling roles of such future-oriented visions. For example, the KBBE agenda shapes European research and innovation priorities in the bio-pharmaceutical sector. It frames socially relevant bio-knowledge in terms of pre-competitive research which can eventually facilitate new commercial products and patentable knowledge. Moreover, the agenda defines new institutional and policy frameworks necessary to realise societal benefits from these products and knowledge

Residual Stress Modelling in Composite Patch Repairs Employing a Cure Kinetics Model with Diffusion Control

Peer reviewed: YesNRC publication: Ye