bluuebunny/crossref_metadata_2025_split huggingface dataset:
O34 Item response theory modeling; old kid on the block to improve pediatric drug dosing
Authors: Krekels EHJ , Välitalo PAJ , Goulooze SC , de Kluis T , van Dijk M , Simons SHP , Tibboel D , Knibbe CAJ 
Published: May 2019

BackgroundQuantification of changes in disease states or clinical conditions is essential to establish drug effects and dosing guidelines. When single endpoints for direct measurements are lacking, multi-factorial observational scales may be used, like for instance pain or sedation scales.1 2MethodsAnalysis of data from multi-factorial observational scales is commonly based on total scores. This assumes each item to be equally informative, which is generally not true. Item Response Theory (IRT), a long existing method in social sciences and psychology, has only recently been recognized for its ideal applicability to the analysis of multi-factorial observational scales. In this approach a latent variable is derived from all item-level data and the information that each item adds to establishing the latent variable is being weighted appropriately. The basic concepts, assumptions and applications of IRT in pharmacological research are introduced and illustrated with examples from studies on analgesia and sedation in the PICU and NICU.ResultsWith IRT modeling, the performance of individual items of the COMFORT and PIPP scales were assessed, and the information or noise that each item adds to the total score was quantified.3 By introducing IRT in a population pharmacokinetic-pharmacodynamic modelling approach, the effect of morphine was establish on both procedural pain in preterm neonates4 and post-operative pain at rest in children [unpublished data]. For this, statistical significance of drug effects were evaluated based on changes in the latent variable and back calculation to the total score of the observational scales allowed for the clinical interpretation of findings.ConclusionIRT offers a desperately needed data analysis framework that may revolutionize pharmacological studies for diseases or conditions that cannot be directly quantified in children. New techniques augmenting the performance of the classical IRT approach when assumptions are violated are currently being developed in our group.Referencesvan Dijk M, de Boer JB, Koot HM Tibboel D, Passchier J, Duivenvoorden HJ. The reliability and validity of the comfort scale as a postoperative pain instrument in 0 to 3-year-old infants. Pain 2000 Feb;84(2–3):367–77.Stevens B, Johnston C, Petryshen P, Taddio A. Premature infant pain profile: development and initial validation. Clin J Pain. 1996 Mar;12(1):13–22.Välitalo PA, van Dijk M, Krekels EH, Gibbins S, Simons SH, Tibboel D, Knibbe CA. Pain and distress caused by endotracheal suctioning in neonates is better quantified by behavioural than physiological items: a comparison based on item response theory modelling. Pain. 2016 Aug;157(8):1611–7.Välitalo PA, Krekels EH, van Dijk M, Simons S, Tibboel D, Knibbe CA. Morphine pharmacodynamics in mechanically ventilated preterm neonates undergoing endotracheal suctioning. CPT Pharmacometrics Syst Pharmacol. 2017 Apr;6(4):239–248Disclosure(s)Nothing to disclose
P32 Depiction of haematological and biochemical laboratory normal reference values in a European multicentre paediatric trial
Authors: Farahani S , Feles E , Burckhardt BB , Laeer S ,   on behalf of the LENA consortium
Published: May 2019

BackgroundThe European multicentre paediatric trials for the drug development programme of LENA (FP7 Grant agreement No. 602295); ‘Labeling of Enalapril from Neonates up to Adolescents’ require the determination of laboratory safety parameters. It was anticipated that the laboratory normal reference values and age range classifications vary depending on the clinical site. Thus, the objective was a seamless and clear depiction of the laboratory parameters to allow an adequate subsequent analysis of data.MethodsFourteen haematological and biochemical safety parameters plus the biomarker N-terminal pro-brain natriuretic peptide were considered. The laboratory normal reference values received from eight clinical sites were screened on data gaps, uncertainties, misclassifications and overlap of age range classifications. These aspects were revised. If further data were necessary for clarification the responsible person of the respective laboratory was contacted by email or telephone.ResultsData gaps and uncertainties of the laboratory normal reference values such as missing data for one sex, missing data for an age range classification, missing data for a parameter or overlap of age range classification were identified. All issues were solved by communication with the sites. Each laboratory parameter was categorized in between 1 and 23 age range classifications between an age from birth to 4744 days depending on the classification of the clinical site. Furthermore, up to 4 various units were recorded per laboratory parameter and subsequently harmonised into one unit.ConclusionThe developed seamless depiction of the laboratory parameters will allow the assessment and classification of the paediatric trial data and are essential for the adequate subsequent analysis.Disclosure(s)Samieh Farahani, Elisabeth Feles, Bjoern B. Burckhardt, Stephanie Laeer declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grand agreement n°602295 (LENA)
P34 Reliable results in continuous bioanalysis of paediatric renin samples – comprehensive quality assessment within clinical studies in children
Authors: Feickert M , Burdman I , Makowski N , Ali M , Farahani S , Majid H , Ciplea AM , Bartel A , Burckhardt BB 
Published: May 2019

BackgroundAs the initiator of the Renin-Angiotensin-Aldosterone-system, renin plays an essential role in the vicious circle of heart failure. Therefore, renin was determined in the investigators driven ‘Labelling of Enalapril from neonates up to adolescents’ (LENA) study to evaluate its role in paediatric heart failure. Due to the often long-lasting periods of recruitment of paediatric subjects, the assay performance has to be guaranteed over the whole recruiting time. Therefore, to ensure the high quality of the determined renin study samples after successful assay validation,1 a multi-step quality approach was used to get reliable results over a period of 30 months.MethodsBased on a multi-step quality approach consisting of calibration standards (CSs), quality controls (QCs) and incurred sample reanalysis (ISR), study samples of unknown renin concentrations were determined. Results within predefined limits of CSs (6 levels) and QCs according to European Medicine Agency (EMA) guidelines were required for evaluating the study samples.2 ISR was performed for randomly selected paediatric samples to evaluate the long-term accuracy of the validated assay.Results133 analytical runs were conducted for renin from February 2016 to August 2018. In 119 (88.8%) valid runs, a total number of 1414 of CCs and 952 of QCs were determined. Thereof 99.9% of CCs and 98.3% of QCs were in the predefined limits according to EMA. 143 incurred sample pairs were reanalysed resulting in 95.8% of samples within EMA guidelines. Using this multi-step quality approach, the reliable determination of 965 LENA paediatric study samples was guaranteed.ConclusionIn addition to the assay validation, the multi-step quality approach ensured the reliability of the determined renin concentrations in the continuous bioanalysis of the paediatric study samples and guaranteed the high quality of the collected data in the LENA study.ReferencesSchaefer J, Burckhardt BB, Tins J, et al. Validated low-volume immunoassay for the reliable determination of direct renin especially valuable for pediatric investigations. J Immunoass Immunochem 2017;38:579–94. doi:10.1080/15321819.2017.1350707Guideline on bioanalytical method validation. European Medicines Agency, London, UK (2011).Disclosure(s)Martin Feickert, Ilja Burdman, Nina Makowski, Moshin Ali, Anke Bartel, and Bjoern B. Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA)
P42 External validation of model-based dosing guidelines for vancomycin, gentamicin and tobramycin in critically ill children
Authors: Hartman S , Zwaag S , Orriëns L , Poel T , de Hoop - Sommen M , de Wildt S 
Published: May 2019

BackgroundPharmacokinetic models are frequently used to simulate dosing strategies for special populations, including critically ill children. The Dutch Pediatric Formulary (DPF) partially bases its guidelines on these models. However, prospective validation of updated dosing regimens is rare. We aimed to identify target attainment and safety of vancomycin, gentamicin and tobramycin after a dose update in the DPF for critically ill neonates and children.MethodsRetropsective cohort study in PICU and NICU patients receiving vancomycin, gentamicin or tobramycin between January 2015 and March 2017 in 2 university hospitals. Demographic clinical laboratory and TDM-data were collected. Target (steady state) trough concentrations for vancomycin, gentamicin and tobramycin used were 10–15, ≤1 and ≤1 mg/l, respectively. Target gentamicin peak concentrations used were 8–12 mg/l.Results486 patients were included in total (165 vancomycin, 97 gentamicin and 224 tobramycin). Trough concentrations of vancomycin, gentamicin and tobramycin were within the target range in 37.5%, 85.3% and 77.2% of patients, respectively. Target attainment of gentamicin peak concentrations in NICU patients was 31%. Non-target trough concentrations were most prevalent in term NICU patients (vancomycin 70%, gentamicin 26% and tobramycin 36.8%). Gentamicin peak concentrations were subtherapeutic in 91% and 45.5% for term and preterm NICU patients, respectively. Creatinine concentrations correlated positively with antibiotic concentrations (correlation coefficient range 0.46–0.54, p≤0.01 in all cohorts).ConclusionDespite recent model-based dosing alterations, sub- and supratherapeutic concentrations of vancomycin, gentamicin and tobramycin are still frequent in critically ill children. Linear dose alterations did offer improvements in target attainment, but did not fully address all relevant covariates that contribute to the large interindividual variation in clearance and/or volume of distribution in these patients. Creatinine clearance was consistently correlated with concentrations of all 3 drugs, but future research is needed to identify whether including this parameter in dosing can improve target attainment and safety.Disclosure(s)Nothing to disclose
P52 Low and erratic exposure of oral acetaminophen in critically ill children determined with a 14C microtracer study: a case for IV acetaminophen for acute pain management?
Authors: Kleiber N , Calvier E , Mooij MG , Krekels EHJ , Vaes WH , Windhorst AD , Hendrikse H , Tibboel D , Knibbe CAJ , de Wildt SN 
Published: May 2019

BackgroundDespite being the most commonly used analgesic and antipyretic, oral APAP bioavailability has not been determined in children. The aim of this study is to compare exposure after oral vs iv APAP using the PK data of the first pediatric oral bioavailability 14C microtracer study.MethodsDesignbioavailability microtracer population PK studyParticipantspatients < 6 yrs old in the pediatric ICU who received 15 mg/kg iv APAP q6hInterventiona single microdose of 14CAPAP (3µg/kg) given orally at the same time as a therapeutic iv doseData collectionBlood was sampled 8 times up to 24 h post-doseData analysispopulation PK analysis using NONMEM. Based on the model, exposure after oral vs iv was compared by simulating the concentration-time profiles and Css (targeted: 10 mg/L ± 20% deviation).3 doses were simulated: 15 mg/kg q6h oral and iv and 22.5 mg/kg oral q6h. 1000 simulations were performed and the percentage of patients reaching the targeted mean Css of 10 mg/L±20% were compared.ResultsOral bioavailibity was 72% (range:11–91%). After 15 mg/kg APAP, the median simulated oral Css was subtherapeutic (6.5 mg/L), but therapeutic (10 mg/L) for IV dosing (15 mg/kg). Patients were 2.5 times less likely to reach therapeutic plasma concentrations with 15 mg/kg oral vs iv APAP.With the maximal recommended oral doses of 22.5 mg/kg 6 h aimed to overcome the 72% bioavailability, median mean Css were therapeutic but overexposure and underexposure were more common than with iv (37 vs 32% Css< 8 mg/L and 30 vs 21% Css>12 mg/L).ConclusionCompared to IV, the usual (15 mg/kg) oral APAP doses result in low systemic exposure with subsequent risk of therapeutic failure. When oral doses are increased to overcome the low bioavailability, underdosing still occurs and overdosing was observed in patients with high bioavailability. IV APAP should therefore be preferred for acute pain management.Disclosure(s)Nothing to disclose
Effect of an integrated neonatal care kit on neonatal health outcomes: a cluster randomised controlled trial in rural Pakistan
Authors: Pell Lisa G , Turab Ali , Bassani Diego G , Shi Joy , Soofi Sajid , Hussain Masawar , Ariff Shabina , Bhutta Zulfiqar A , Morris Shaun K 
Published: May 2019

IntroductionIn 2016, 2.6 million children died during their first month of life. We assessed the effectiveness of an integrated neonatal care kit (iNCK) on neonatal survival and other health outcomes in rural Pakistan.MethodsWe conducted a community-based, cluster randomised, pragmatic, open-label, controlled intervention trial in Rahim Yar Khan, Punjab, Pakistan. Clusters, 150 villages and their lady health workers (LHWs), were randomly assigned to deliver the iNCK (intervention) or standard of care (control). In intervention clusters, LHWs delivered the iNCK and education on its use to pregnant women. The iNCK contained a clean birth kit, chlorhexidine, sunflower oil, a continuous temperature monitor (ThermoSpot), a heat reflective blanket and reusable heat pack. LHWs were also given a hand-held scale. The iNCK was implemented primarily by caregivers. The primary outcome was all-cause neonatal mortality. Outcomes are reported at the individual level, adjusted for cluster allocation. Enrolment took place between April 2014 and July 2015 and participant follow-up concluded in August 2015.Results5451 pregnant women (2663 and 2788 in intervention and control arms, respectively) and their 5286 liveborn newborns (2585 and 2701 in intervention and control arms, respectively) were enrolled. 147 newborn deaths were reported, 65 in the intervention arm (25.4 per 1000 live births) compared with 82 in the control arm (30.6 per 1000 live births). Neonatal mortality was not significantly different between treatment groups (risk ratio 0.83, 95% CI 0.58 – 1.18; p = 0.30).ConclusionProviding co-packaged interventions directly to women did not significantly reduce neonatal mortality. Further research is needed to improve compliance with intended iNCK use.
Menopause and FOXP3+ Treg cell depletion eliminate female protection against T cell-mediated angiotensin II hypertension
Authors: Pollow Dennis P. , Uhlorn Joshua A. , Sylvester Megan A. , Romero-Aleshire Melissa J. , Uhrlaub Jennifer L. , Lindsey Merry L. , Nikolich-Zugich Janko , Brooks Heddwen L. 
Published: May 2019

Although it is known that the prevalence and severity of hypertension increases in women after menopause, the contribution of T cells to this process has not been explored. Although the immune system is both necessary and required for the development of angiotensin II (ANG II) hypertension in men, we have demonstrated that premenopausal women are protected from T cell-mediated hypertension. The goal of the current study was to test the hypotheses that 1) female protection against T cell-mediated ANG II hypertension is eliminated following progression into menopause and 2) T regulatory cells (Tregs) provide premenopausal protection against ANG II-induced hypertension. Menopause was induced in Rag-1−/− mice (via 4-vinylcyclohexene diepoxide), and all mice received a 14-day ANG II infusion. Donor CD3+ T cells were adoptively transferred 3 wk before ANG II infusion. In the absence of T cells, systolic blood pressure responses to ANG II were similar to those seen in premenopausal mice (Δ12 mmHg). After adoptive transfer of T cells, ANG II significantly increased systolic blood pressure in postmenopausal females (Δ28 mmHg). A significant increase in F4/80 positive renal macrophages, an increase in renal inflammatory gene expression, along with a reduction in renal expression of mannose receptor C-type 1, a marker for M2 macrophages, accompanied the increase in systolic blood pressure (SBP). Flow cytometric analysis identified that Tregs were significantly decreased in the spleen and kidneys of Rag-1−/− menopausal mice versus premenopausal females, following ANG II infusion. In a validation study, an anti-CD25 antibody was used to deplete Tregs in premenopausal mice, which induced a significant increase in SBP. These results demonstrate that premenopausal protection against T cell-mediated ANG II hypertension is eliminated once females enter menopause, suggesting that a change in hormonal status upregulates macrophage-induced proinflammatory and T cell-dependent responses. Furthermore, we are the first to report that the presence of Tregs are required to suppress ANG II hypertension in premenopausal females. NEW & NOTEWORTHY Whether progression into menopause eliminated female protection against T cell-mediated hypertension was examined. Menopausal mice without T cells remained protected against angiotensin II (ANG II) hypertension; however, in the presence of T cells, blood pressure responses to ANG II increased significantly in menopause. Underlying mechanisms examined were anti-inflammatory protection provided by T regulatory cells in premenopausal females and renal inflammatory processes involving macrophage infiltration and cytokine activation.
Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk: A Transcriptome-Wide Association Study in Over 140,000 European Descendants
Authors: Wu Lang , Wang Jifeng , Cai Qiuyin , Cavazos Taylor B. , Emami Nima C. , Long Jirong , Shu Xiao-Ou , Lu Yingchang , Guo Xingyi , Bauer Joshua A. , Pasaniuc Bogdan , Penney Kathryn L. , Freedman Matthew L. , Kote-Jarai Zsofia , Witte John S. , Haiman Christopher A. , Eeles Rosalind A. , Zheng Wei 
Published: May 2019

Abstract

Genome-wide association study–identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P &lt; 2.61 × 10−6, a Bonferroni-corrected threshold, including nine genes that remained significant at P &lt; 2.61 × 10−6 after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology.

Significance:
This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer.
Inhibition of ATM Increases Interferon Signaling and Sensitizes Pancreatic Cancer to Immune Checkpoint Blockade Therapy
Authors: Zhang Qiang , Green Michael D. , Lang Xueting , Lazarus Jenny , Parsels Joshua D. , Wei Shuang , Parsels Leslie A. , Shi Jiaqi , Ramnath Nithya , Wahl Daniel R. , Pasca di Magliano Marina , Frankel Timothy L. , Kryczek Ilona , Lei Yu L. , Lawrence Theodore S. , Zou Weiping , Morgan Meredith A. 
Published: May 2019

Abstract

Combinatorial strategies are needed to overcome the resistance of pancreatic cancer to immune checkpoint blockade (ICB). DNA damage activates the innate immune response and improves ICB efficacy. Because ATM is an apical kinase in the radiation-induced DNA damage response, we investigated the effects of ATM inhibition and radiation on pancreatic tumor immunogenicity. ATM was inhibited through pharmacologic and genetic strategies in human and murine pancreatic cancer models both in vitro and in vivo. Tumor immunogenicity was evaluated after ATM inhibition alone and in combination with radiation by assessing TBK1 and Type I interferon (T1IFN) signaling as well as tumor growth following PD-L1/PD-1 checkpoint inhibition. Inhibition of ATM increased tumoral T1IFN expression in a cGAS/STING-independent, but TBK1- and SRC-dependent, manner. The combination of ATM inhibition with radiation further enhanced TBK1 activity, T1IFN production, and antigen presentation. Furthermore, ATM silencing increased PD-L1 expression and increased the sensitivity of pancreatic tumors to PD-L1–blocking antibody in association with increased tumoral CD8+ T cells and established immune memory. In patient pancreatic tumors, low ATM expression inversely correlated with PD-L1 expression. Taken together, these results demonstrate that the efficacy of ICB in pancreatic cancer is enhanced by ATM inhibition and further potentiated by radiation as a function of increased tumoral immunogenicity, underscoring the potential of ATM inhibition in combination with ICB and radiation as an efficacious treatment strategy for pancreatic cancer.

Significance:
This study demonstrates that ATM inhibition induces a T1IFN-mediated innate immune response in pancreatic cancer that is further enhanced by radiation and leads to increased sensitivity to anti–PD-L1 therapy.
See related commentary by Gutiontov and Weichselbaum, p. 3815
Is There a Right to Human Dignity? The Example of the Right to Education of Refugees
Authors: Konsta Anna-Maria 
Published: May 2019

Abstract
The present article attempts a brief presentation of the legal framework in relation to the protection of the right to education and the protection of the human dignity of refugees, with reference to international and emphasis on European law, in an effort to recognize the inviolability of the right to education of refugees. At the same time, the question is raised if there is an independent right to human dignity or if human dignity is merely a framework term in light of which one could interpret, for example, the right to education of refugees. Through the discussed case-law of the European judicial and quasi-judicial bodies, which use the concept of human dignity, in order to protect asylum seekers, a European concept of human dignity has emerged, which may be acknowledged as an absolute fundamental right.