Prospectie met ingreep in de bodem aan de Bilzerbaan te Lanaken (Veldwezelt)

Dit rapport werd ingediend bij het agentschap samen met een aantal afzonderlijke digitale bijlagen. Een aantal van deze bijlagen zijn niet inbegrepen in dit pdf document en zijn niet online beschikbaar. Sommige bijlagen (grondplannen, fotos, spoorbeschrijvingen, enz.) kunnen van belang zijn voor een betere lezing en interpretatie van dit rapport. Indien u deze bijlagen wenst te raadplegen kan u daarvoor contact opnemen met: [email protected]

Prospectie met ingreep in de bodem aan de Oude Tramstraat te Gingelom

Dit rapport werd ingediend bij het agentschap samen met een aantal afzonderlijke digitale bijlagen. Een aantal van deze bijlagen zijn niet inbegrepen in dit pdf document en zijn niet online beschikbaar. Sommige bijlagen (grondplannen, fotos, spoorbeschrijvingen, enz.) kunnen van belang zijn voor een betere lezing en interpretatie van dit rapport. Indien u deze bijlagen wenst te raadplegen kan u daarvoor contact opnemen met: [email protected]

Archeologische opgraving aan de Industrieweg te Lanaken

Dit rapport werd ingediend bij het agentschap samen met een aantal afzonderlijke digitale bijlagen. Een aantal van deze bijlagen zijn niet inbegrepen in dit pdf document en zijn niet online beschikbaar. Sommige bijlagen (grondplannen, fotos, spoorbeschrijvingen, enz.) kunnen van belang zijn voor een betere lezing en interpretatie van dit rapport. Indien u deze bijlagen wenst te raadplegen kan u daarvoor contact opnemen met: [email protected]

Individualized dosing algorithms for tacrolimus in kidney transplant recipients:current status and unmet needs

Introduction: Tacrolimus is a potent immunosuppressive drug with many side effects including nephrotoxicity and post-transplant diabetes mellitus. To limit its toxicity, therapeutic drug monitoring (TDM) is performed. However, tacrolimus’ pharmacokinetics are highly variable within and between individuals, which complicates their clinical management. Despite TDM, many kidney transplant recipients will experience under- or overexposure to tacrolimus. Therefore, dosing algorithms have been developed to limit the time a patient is exposed to off-target concentrations. Areas Covered: Tacrolimus starting dose algorithms and models for follow-up doses developed and/or tested since 2015, encompassing both adult and pediatric populations. Literature was searched in different databases, i.e. Embase, PubMed, Web of Science, Cochrane Register, and Google Scholar, from inception to February 2023 Expert Opinion: Many algorithms have been developed, but few have been prospectively evaluated. These performed better than bodyweight-based starting doses, regarding the time a patient is exposed to off-target tacrolimus concentrations. No benefit in reduced tacrolimus toxicity has yet been observed. Most algorithms were developed from small datasets, contained only a few tacrolimus concentrations per person, and were not externally validated. Moreover, other matrices should be considered which might better correlate with tacrolimus toxicity than the whole-blood concentration, e.g. unbound plasma or intra-lymphocytic tacrolimus concentrations.</p

Population Pharmacokinetic Modelling of Intravenous Immunoglobulin Treatment in Patients with Guillain–Barré Syndrome

BACKGROUND AND OBJECTIVE: Intravenous immunoglobulin (IVIg) at a standard dosage is the treatment of choice for Guillain–Barré syndrome. The pharmacokinetics, however, is highly variable between patients, and a rapid clearance of IVIg is associated with poor recovery. We aimed to develop a model to predict the pharmacokinetics of a standard 5-day IVIg course (0.4 g/kg/day) in patients with Guillain–Barré syndrome. METHODS: Non-linear mixed-effects modelling software (NONMEM(®)) was used to construct a pharmacokinetic model based on a model-building cohort of 177 patients with Guillain–Barré syndrome, with a total of 589 sequential serum samples tested for total immunoglobulin G (IgG) levels, and evaluated on an independent validation cohort that consisted of 177 patients with Guillain–Barré syndrome with 689 sequential serum samples. RESULTS: The final two-compartment model accurately described the daily increment in serum IgG levels during a standard IVIg course; the initial rapid fall and then a gradual decline to steady-state levels thereafter. The covariates that increased IgG clearance were a more severe disease (as indicated by the Guillain–Barré syndrome disability score) and concomitant methylprednisolone treatment. When the current dosing regimen was simulated, the percentage of patients who reached a target ∆IgG > 7.3 g/L at 2 weeks decreased from 74% in mildly affected patients to only 33% in the most severely affected and mechanically ventilated patients (Guillain–Barré syndrome disability score of 5). CONCLUSIONS: This is the first population-pharmacokinetic model for standard IVIg treatment in Guillain–Barré syndrome. The model provides a new tool to predict the pharmacokinetics of alternative regimens of IVIg in Guillain–Barré syndrome to design future trials and personalise treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-022-01136-z

Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling

The Gram-negative anaerobe Porphyromonas gingivalis is associated with chronic periodontitis. Clinical isolates of P. gingivalis strains with high dipeptidyl peptidase 4 (DPP4) expression also had a high capacity for biofilm formation and were more infective. The X-ray crystal structure of P. gingivalis DPP4 was solved at 2.2 Å resolution. Despite a sequence identity of 32%, the overall structure of the dimer was conserved between P. gingivalis DPP4 and mammalian orthologues. The structures of the substrate binding sites were also conserved, except for the region called S2-extensive, which is exploited by specific human DPP4 inhibitors currently used as antidiabetic drugs. Screening of a collection of 450 compounds as inhibitors revealed a structure-activity relationship that mimics in part that of mammalian DPP9. The functional similarity between human and bacterial DPP4 was confirmed using 124 potential peptide substrates

Towards precision dosing of aripiprazole in children and adolescents with autism spectrum disorder:Linking blood levels to weight gain and effectiveness

Aims: Aripiprazole is one of the most commonly prescribed antipsychotic drugs to children and adolescents worldwide, but it is associated with serious side-effects, including weight gain. This study assessed the population pharmacokinetics of aripiprazole and its active metabolite and investigated the relationship between pharmacokinetic parameters and body mass index (BMI) in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side-effects and drug effectiveness. Methods: Twenty-four children and adolescents (15 males, 9 females) aged 6–18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side-effects and drug effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were determined. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 92 aripiprazole and 91 dehydro-aripiprazole concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-h area under the curves (AUCs) were analysed to predict outcomes using generalized and linear mixed-effects models. Results: For both aripiprazole and dehydro-aripiprazole, one-compartment models best described the measured concentrations, with albumin and BMI as significant covariates. Of all the pharmacokinetic parameters, higher sum (aripiprazole plus dehydro-aripiprazole) trough concentrations best predicted higher BMI z-scores (P &lt;.001) and higher Hb1Ac levels (P =.03) during follow-up. No significant association was found between sum concentrations and effectiveness. Conclusions: Our results indicate a threshold with regard to safety, which suggests that therapeutic drug monitoring of aripiprazole could potentially increase safety in children and adolescents with ASD and behavioural problems.</p

Morphological and functional evaluation of the bioresorption of the bioresorbable everolimus-eluting vascular scaffold using IVUS, echogenicity and vasomotion testing at two year follow-up: a patient level insight into the ABSORB A clinical trial

The aim of this study was to describe vaso-reactivity (by Acetylcholine and Methergine tests) at 2 year follow-up in parallel with the individual changes in the echogenicity characteristics of the polymer struts of the everolimus eluting bioresorbable vascular scaffold (BVS), from post-treatment to 2 year follow-up, in patients enrolled in the ABSORB Cohort A study. Intravascular ultrasound assessment was performed with a phased array catheter (EagleEye, Volcano Corporation, Cordova, CA, USA) with automated pullback at 0.5 mm per second. The % ratio at 6 months and 2 years [(Scaffold Area post PCI- Lumen Area)/Scaffold Area post PCI] was calculated as a measure of scaffold shrinkage. The % change of hyperechogenicity was defined as: ([post-procedural hyperechogenicity] - [2 year follow up hyperechogenicity])/[post-procedural hyperechogenicity]) × 100. The vasomotion test with intracoronary acetylcholine (10-6M) or intravenous methergine (0.4 mg) was performed at 2 years. Overall nine patients received all these analyses and were enrolled in the present analysis. A 50-96% reduction in hyperechogenicity was observed between baseline and 2 years, which corresponded to a change in vasoreactivity between 2 and 22%. A vasoconstriction of the scaffolded segment was observed in the 5 patients, who underwent the methergine test, with a mean decrease in lumen diameter after met

Comparison of DNA methylation patterns of parentally imprinted genes in placenta derived from IVF conceptions in two different culture media

Study question: Is there a difference in DNA methylation status of imprinted genes in placentas derived from IVF conceptions where embryo culture was performed in human tubal fluid (HTF) versus G5 culture medium? Summary answer: We found no statistically significant differences in the mean DNA methylation status of differentially methylated regions (DMRs) associated with parentally imprinted genes in placentas derived from IVF conceptions cultured in HTF versus G5 culture medium. What is known already: Animal studies indicate that the embryo culture environment affects the DNA methylation status of the embryo. In humans, birthweight is known to be affected by the type of embryo culture medium used. The effect of embryo culture media on pregnancy, birth and child development may thus be mediated by differential methylation of parentally imprinted genes in the placenta. Study design, size, duration: To identify differential DNA methylation of imprinted genes in human placenta derived from IVF conceptions exposed to HTF or G5 embryo culture medium, placenta samples (n = 43 for HTF, n = 54 for G5) were collected between 2010 and 2012 s as part of a multi-center randomized controlled trial in the Netherlands comparing these embryo culture media. Placenta samples from 69 naturally conceived (NC) live births were collected during 2008-2013 in the Netherlands as reference material. Participants/materials, setting, methods: To identify differential DNA methylation of imprinted genes, we opted for an amplicon-based sequencing strategy on an Illumina MiSeq sequencing platform. DNA was isolated and 34 DMRs associated with well-defined parentally imprinted genes were amplified in a two-step PCR before sequencing using MiSeq technology. Sequencing data were analyzed in a multivariate fashion to eliminate possible confounding effects. Main results and the role of chance: We found no statistically significant differences in the mean DNA methylation status of any of the imprinted DMRs in placentas derived from IVF conceptions cultured in HTF or G5 culture medium. We also did not observe any differences in the mean methylation status per amplicon nor in the variance in methylation per amplicon between the two culture medium groups. A separate surrogate variable analysis also demonstrated that the IVF culture medium was not associated with the DNA methylation status of these DMRs. The mean methylation level and variance per CpG was equal between HTF and G5 placenta. Additional comparison of DNA methylation status of NC placenta samples revealed no statistically significant differences in mean amplicon and CpG methylation between G5, HTF and NC placenta; however, the number of placenta samples exhibiting outlier methylation levels was higher in IVF placenta compared to NC (P < 0.00001). Also, we were able to identify 37 CpG sites that uniquely displayed outlier methylation in G5 placentas and 32 CpG sites that uniquely displayed outlier methylation in HTF. In 8/37 (G5) and 4/32 (HTF) unique outliers CpGs, a medium-specific unique outlier could be directly correlated to outlier methylation of the entire amplicon. Limitations, reasons for caution: Due to practical reasons, not all placentas were collected during the trial, and we collected the placentas from natural conceptions from a different cohort, potentially creating bias. We limited ourselves to the DNA methylation status of 34 imprinted DMRs, and we studied only the placenta and no other embryo-derived tissues. Wider implications of the findings: It has often been postulated, but has yet to be rigorously tested, that imprinting mediates the effects of embryo culture conditions on pregnancy, birth and child development in humans. Since we did not detect any statistically significant effects of embryo culture conditions on methylation status of imprinted genes in the placenta, this suggests that other unexplored mechanisms may underlie these effects. The biological and clinical relevance of detected outliers with respect to methylation levels of CpGs and DMR require additional analysis in a larger sample size as well. Given the importance and the growing number of children born through IVF, research into these molecular mechanisms is urgently needed. Study funding/competing interest(s): This study was funded by the March of Dimes grant number #6-FY13-153. The authors have no conflicts of interest. Trial registration number: Placental biopsies were obtained under Netherlands Trial Registry number 1979 and 1298

Basic Science Fully Automatic Three-Dimensional Quantitative Analysis of Intracoronary Optical Coherence Tomography: Method and Validation

Objectives and background: Quantitative analysis of intracoronary optical coherence tomography (OCT) image data (QOCT) is currently performed by a time-consuming manual contour tracing process in individual OCT images acquired during a pullback procedure (frame-based method). To get an efficient quantitative analysis process, we developed a fully automatic three-dimensional (3D) lumen contour detection method and evaluated the results against those derived by expert human observers. Methods: The method was developed using Matlab (The Mathworks, Natick, MA). It incorporates a graphical user interface for contour display and, in the selected cases where this might be necessary, editing. OCT image data of 20 randomly selected patients, acquired with a commercially available system (Lightlab imaging, Westford, MA), were pulled from our OCT database for validation. Results: A total of 4,137 OCT images were analyzed. There was no statistically significant difference in mean lumen areas between the two methods (5.03 6 2.16 vs. 5.02 6 2.21 mm 2 ; P 5 0.6, human vs. automated). Regression analysis showed a good correlation with an r value of 0.99. The method requires an average 2-5 sec calculation time per OCT image. In 3% of the detected contours an observer correction was necessary. Conclusion: Fully automatic lumen contour detection in OCT images is feasible with only a select few contours showing an artifact (3%) that can be easily corrected. This QOCT method may be a valuable tool for future coronary imaging studies incorporating OCT