Publications by authors named "Jacobs An"

61 Publications

Recalcitrant Flexor Hallucis Longus Dysfunction: A Case Study Demonstrating the Successful Application of an Adaptable Rehabilitation Program With a Two-Year Follow-Up.

Cureus 2021 Apr 6;13(4):e14326. Epub 2021 Apr 6.

Radiology, Brook Army Medical Center, San Antonio, USA.

Flexor hallucis longus (FHL) dysfunction is a condition experienced primarily by athletes, including ballet dancers and runners. Accurate diagnosis and definitive treatment at the initial evaluation can often be difficult given the number of foot and ankle pathologies that share similar signs and symptoms. The evaluation process tends to be a diagnosis of inclusion rather than a specific pathology with an accepted rehabilitation plan. For example, patients with medial arch pain may undergo an extended rehabilitation period with an evolving differential diagnosis requiring several treatment modifications. A more appropriate rehabilitation paradigm should adapt to the potential changes in patient symptoms and presentation, addressing functional impairments as they arise. This case study describes the successful management of a patient with chronic FHL dysfunction, leveraging a flexible, multimodal treatment approach to address the evolving functional impairments rather than focusing on a single, discrete diagnosis. At a two-year follow-up, the patient remains pain-free.
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http://dx.doi.org/10.7759/cureus.14326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159326PMC
April 2021

An in vitro air-liquid interface inhalation platform for petroleum substances and constituents.

ALTEX 2021 04 20. Epub 2021 Apr 20.

VITO NV (Flemish Institute for Technological Research), Unit HEALTH, Mol, Belgium.

The goal is to optimize and show the validity of an in vitro method for inhalation testing of petroleum substances and its constituents at the air-liquid interface (ALI). The approach is demonstrated in a pilot study with ethylbenzene (EB), a mono-constituent petroleum substance using a human alveolar epithelial cell line model. This included the development and validation of a generation facility to obtain EB vapors and the optimization of an exposure system for a negative control (clean air, CA), positive control (nitrogen dioxide), and EB vapors. The optimal settings for the VITROCELL® 24/48 system were defined. Cytotoxicity, cell viability, inflammation, and oxidative stress were assessed in A549 after exposure to EB vapors. A concentration-dependent significant decrease in mean cell viability was observed after exposure, which was confirmed by a cytotoxicity test. The oxidative stress marker superoxide dismutase 2 was significantly increased, but no concentration-response was observed. A concentration-dependent significant increase in pro-inflammatory markers C-C motif chemokine ligand 2, interleukin (IL)6, and IL8 was observed for EB-exposed A549 cells compared to CA. The data demonstrated consistency between in vivo air concentrations at which adverse respiratory effects were observed and ALI-concentrations affecting cell viability, provided that the actual measured in vitro delivery efficiency of the compound were included. It can be concluded that extrapolating in vitro air concentrations (adjusted for delivery efficiency and absorption characteristics and applied for testing cell viability) to simulate in vivo air concentrations may be a promising method to screen for acute inhalation toxicity.
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http://dx.doi.org/10.14573/altex.2010211DOI Listing
April 2021

Release and cytotoxicity screening of the printer emissions of a CdTe quantum dots-based fluorescent ink.

Toxicol Lett 2021 Sep 18;347:1-11. Epub 2021 Apr 18.

LEITAT Technological Center, Carrer de la Innovació 2, 08225, Terrassa, Barcelona, Spain. Electronic address:

The fluorescent properties of cadmium telluride (CdTe) containing quantum dots (QDs) have led to novel products and applications in the ink and pigment industry. The toxic effects of the emissions associated to the use of printing ink containing CdTe QDs might differ from those of conventional formulations which do not integrate nanoparticles, as CdTe QDs might be emitted. Within this work, the airborne emissions of a water-soluble fluorescent ink containing polyethylene glycol (PEG)-coated CdTe QDs of 3-5 nm diameter have been characterized and studied under controlled conditions during household inkjet printing in a scenario simulating the use phase. Subsequently, the cytotoxicological potential of atomized CdTe QDs ink in an acute exposure regimen simulating an accidental, worse-case scenario has been evaluated in vitro at the air-liquid interface (ALI) using the pulmonary cell line BEAS-2B. Endpoints screened included cell viability, oxidative stress and inflammatory effects. We have observed that CdTe QDs ink at 54.7 ng/mL decreased cell viability by 25.6 % when compared with clean air after 1h of exposure; a concentration about 65 times higher was needed to observe a similar effect in submerged conditions. However, we did not observe oxidative stress or inflammatory effects. The present study integrates the development of scenarios simulating the use phase of nano-additivated inks and the direct cell exposure for in vitro effects assessment, thus implementing a life-cycle oriented approach in the assessment of the toxicity of CdTe QDs.
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http://dx.doi.org/10.1016/j.toxlet.2021.04.009DOI Listing
September 2021

Augmented Reality-Assisted Neurosurgical Drain Placement (ARANED): Technical Note.

Acta Neurochir Suppl 2021 ;131:267-273

Department of Neurosurgery, UZ Brussel, Jette, Belgium.

Background: Many surgical procedures, such as placement of intracranial drains, are currently being performed blindly, relying on anatomical landmarks. As a result, accuracy results still have room for improvement. Neuronavigation could address this issue, but its application in an urgent setting is often impractical. Augmented reality (AR) provided through a head-worn device has the potential to tackle this problem, but its implementation should meet physicians' needs.

Methods: The Surgical Augmented Reality Assistance (SARA) project aims to develop an AR solution that is suitable for preoperative planning, intraoperative visualisation and navigational support in an everyday clinical setting, using a Microsoft HoloLens.

Results: Proprietary hardware and software adaptations and dedicated navigation algorithms are applied to the Microsoft HoloLens to optimise it specifically for neurosurgical navigation. This includes a pipeline with an additional set of advanced, semi-automated algorithms responsible for image processing, hologram-to-patient registration and intraoperative tracking using infrared depth-sensing. A smooth and efficient workflow while maintaining high accuracy is prioritised. The AR solution provides a fully integrated and completely mobile navigation setup. Initial preclinical and clinical validation tests applying the solution to intracranial drain placement are described.

Conclusion: AR has the potential to vastly increase accuracy of everyday procedures that are frequently performed without image guidance, but could still benefit from navigational support, such as intracranial drain placements. Technical development should go hand in hand with preclinical and clinical validation in order to demonstrate improvements in accuracy and clinical outcomes.
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http://dx.doi.org/10.1007/978-3-030-59436-7_50DOI Listing
June 2021

Phosphodiesterase 1C integrates store-operated calcium entry and cAMP signaling in leading-edge protrusions of migrating human arterial myocytes.

J Biol Chem 2021 Mar 28:100606. Epub 2021 Mar 28.

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. Electronic address:

In addition to maintaining cellular ER Ca stores, store-operated Ca entry (SOCE) regulates several Ca-sensitive cellular enzymes, including certain adenylyl cyclases (ADCYs), enzymes that synthesize the secondary messenger cAMP. Ca, acting with calmodulin (CaM), can also increase the activity of PDE1-family phosphodiesterases (PDEs), which cleave the phosphodiester bond of cAMP. Surprisingly, SOCE regulated cAMP signaling has not been studied in cells expressing both Ca-sensitive enzymes. Here, we report that depletion of ER Ca activates PDE1C in human arterial smooth muscle cells (HASMCs). Inhibiting the activation of PDE1C reduced the magnitude of both SOCE and subsequent Ca/CaM-mediated activation of ADCY8 in these cells. Since inhibiting or silencing Ca-insensitive PDEs had no such effects, these data identify PDE1C-mediated hydrolysis of cAMP as a novel and important link between SOCE and its activation of ADCY8. Functionally, we showed that PDE1C regulated the formation of leading-edge protrusions (LEPs) in HASMCs, a critical early event in cell migration. Indeed, we found that PDE1C populated the tips of newly forming LEPs in polarized HASMCs, and co-localized with ADCY8, the Ca release-activated Ca channel subunit, Orai1, the cAMP-effector, PKA, and an A-kinase anchoring protein, AKAP79. Since this polarization could allow PDE1C to control cAMP signaling in a hyper-localized manner, we suggest that PDE1C-selective therapeutic agents could offer increased spatial specificity in HASMCs over agents that regulate cAMP globally in cells. Similarly, such agents could also prove useful in regulating crosstalk between Ca/cAMP signaling in other cells in which dysregulated migration contributes to human pathology, including certain cancers.
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http://dx.doi.org/10.1016/j.jbc.2021.100606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095186PMC
March 2021

Postoperative Cerebral Oxygen Saturation in Children After Congenital Cardiac Surgery and Long-Term Total Intelligence Quotient: A Prospective Observational Study.

Crit Care Med 2021 06;49(6):967-976

All authors: Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, UZ Leuven and KU Leuven, Leuven, Belgium.

Objectives: During the early postoperative period, children with congenital heart disease can suffer from inadequate cerebral perfusion, with possible long-term neurocognitive consequences. Cerebral tissue oxygen saturation can be monitored noninvasively with near-infrared spectroscopy. In this prospective study, we hypothesized that reduced cerebral tissue oxygen saturation and increased intensity and duration of desaturation (defined as cerebral tissue oxygen saturation < 65%) during the early postoperative period, independently increase the probability of reduced total intelligence quotient, 2 years after admission to a PICU.

Design: Single-center, prospective study, performed between 2012 and 2015.

Setting: The PICU of the University Hospitals Leuven, Belgium.

Patients: The study included pediatric patients after surgery for congenital heart disease admitted to the PICU.

Interventions: None.

Measurements And Main Results: Postoperative cerebral perfusion was characterized with the mean cerebral tissue oxygen saturation and dose of desaturation of the first 12 and 24 hours of cerebral tissue oxygen saturation monitoring. The independent association of postoperative mean cerebral tissue oxygen saturation and dose of desaturation with total intelligence quotient at 2-year follow-up was evaluated with a Bayesian linear regression model adjusted for known confounders. According to a noninformative prior, reduced mean cerebral tissue oxygen saturation during the first 12 hours of monitoring results in a loss of intelligence quotient points at 2 years, with a 90% probability (posterior β estimates [80% credible interval], 0.23 [0.04-0.41]). Similarly, increased dose of cerebral tissue oxygen saturation desaturation would result in a loss of intelligence quotient points at 2 years with a 90% probability (posterior β estimates [80% credible interval], -0.009 [-0.016 to -0.001]).

Conclusions: Increased dose of cerebral tissue oxygen saturation desaturation and reduced mean cerebral tissue oxygen saturation during the early postoperative period independently increase the probability of having a lower total intelligence quotient, 2 years after PICU admission.
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http://dx.doi.org/10.1097/CCM.0000000000004852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132917PMC
June 2021

A Novel Approach to Assessing and Treating Musculoskeletal-Mediated Atypical Abdominal Pain: A Case Study.

Cureus 2020 Dec 29;12(12):e12359. Epub 2020 Dec 29.

Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, USA.

Abdominal pain is a common and functionally limiting complaint within the healthcare system linked to impaired quality of life and increased health care utilization. This chief complaint is associated with an extensive differential diagnosis leading to high utilization of diagnostic testing, increased healthcare cost, and delayed access to care. In patients presenting with acute or chronic abdominal pain, musculoskeletal pain often requires expensive testing, thereby delaying definitive care. An improved triage process is warranted. Performing a musculoskeletal examination to determine if pain patterns can be mechanically reproduced at the site of origin, or remote to the site of pain, warrants referral to a musculoskeletal specialist. In our young and healthy population, once the musculoskeletal mediated abdominal pain origin is determined, we see significant success in the application of a treatment approach consisting of manipulative therapy, exercise, and instrument-assisted soft tissue mobilization. A multimodal treatment approach for musculoskeletal-mediated abdominal pain has not been previously described. This case study outlines a novel management approach for musculoskeletal-mediated abdominal pain and provides an alternative diagnostic technique, when implemented early in the evaluation and management process of atypical abdominal pain, that improves the quality of life.
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http://dx.doi.org/10.7759/cureus.12359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839810PMC
December 2020

Passive Shoulder Exoskeletons: More Effective in the Lab Than in the Field?

IEEE Trans Neural Syst Rehabil Eng 2021 26;29:173-183. Epub 2021 Feb 26.

Shoulder exoskeletons potentially reduce overuse injuries in industrial settings including overhead work or lifting tasks. Previous studies evaluated these devices primarily in laboratory setting, but evidence of their effectiveness outside the lab is lacking. The present study aimed to evaluate the effectiveness of two passive shoulder exoskeletons and explore the transfer of laboratory-based results to the field. Four industrial workers performed controlled and in-field evaluations without and with two exoskeletons, ShoulderX and Skelex in a randomized order. The exoskeletons decreased upper trapezius activity (up to 46%) and heart rate in isolated tasks. In the field, the effects of both exoskeletons were less prominent (up to 26% upper trapezius activity reduction) while lifting windscreens weighing 13.1 and 17.0 kg. ShoulderX received high discomfort scores in the shoulder region and usability of both exoskeletons was moderate. Overall, both exoskeletons positively affected the isolated tasks, but in the field the support of both exoskeletons was limited. Skelex, which performed worse in the isolated tasks compared to ShoulderX, seemed to provide the most support during the in-field situations. Exoskeleton interface improvements are required to improve comfort and usability. Laboratory-based evaluations of exoskeletons should be interpreted with caution, since the effect of an exoskeleton is task specific and not all in-field situations with high-level lifting will equally benefit from the use of an exoskeleton. Before considering passive exoskeleton implementation, we recommend analyzing joint angles in the field, because the support is inherently dependent on these angles, and to perform in-field pilot tests. This paper is the first thorough evaluation of two shoulder exoskeletons in a controlled and in-field situation.
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http://dx.doi.org/10.1109/TNSRE.2020.3041906DOI Listing
February 2021

Proximal Humerus Fracture Following Arthroscopic Biceps Tenodesis.

J Orthop Sports Phys Ther 2020 11;50(11):649

A 60-year-old woman with chronic atraumatic shoulder pain underwent arthroscopic biceps tenodesis. Upon presenting to the physical therapy clinic 7 days following surgery, she reported constant pain. Following the examination, the physical therapist reviewed the patient's postoperative radiographs and noted a comminuted but minimally displaced fracture of the right proximal humeral metaphysis. .
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http://dx.doi.org/10.2519/jospt.2020.9497DOI Listing
November 2020

Alternative air-liquid interface method for inhalation toxicity testing of a petroleum-derived substance.

MethodsX 2020 8;7:101088. Epub 2020 Oct 8.

VITO NV (Flemish Institute for Technological Research), Unit HEALTH, Mol, Belgium.

-based new approach methodologies (NAMs) provide a pragmatic solution to animal testing of petroleum substances and their constituents. A previous study exposed an in vitro model (A549 cells) at the air-liquid interface (ALI) to assess inhalation toxicity of a single compound, ethylbenzene. Experimental conditions using VITROCELL 24/48 exposure system were optimized to achieve a deposition efficiency that resulted in dose-dependent biological changes. The feasibility of this set-up was evaluated for testing the complex substance gasoline, which, at only high concentrations, can induce mild respiratory irritation in animals and cough in humans.•Results showed that perpendicular ALI exposure flow systems (VITROCELL® 6/4 and 24/48) may not be appropriate for testing gasoline because it was not possible to achieve enough deposition onto the cells and in the culture medium to measure dose and to determine dose-dependent biological changes (more information can be found in 'Supplementary material and/or Additional information' section).•Structural features ( aromatic or saturated hydrocarbon structure) and high hydrophobicity, together with the low concentrations of individual components in gasoline, may have caused the low deposition.•To achieve a higher deposition on the cells, A549 cells were exposed to gasoline at the ALI by passive dosing.The results demonstrate that the presented methodology is a promising NAM for inhalation toxicity testing of (semi-)volatile complex substances with low aqueous solubility.
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http://dx.doi.org/10.1016/j.mex.2020.101088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581970PMC
October 2020

Improving Quality in Nanoparticle-Induced Cytotoxicity Testing by a Tiered Inter-Laboratory Comparison Study.

Nanomaterials (Basel) 2020 Jul 22;10(8). Epub 2020 Jul 22.

ECAMRICERT SRL, European Center for the Sustainable Impact of Nanotechnology (ECSIN), Corso Stati Uniti 4, 35127 Padova, Italy.

The quality and relevance of nanosafety studies constitute major challenges to ensure their key role as a supporting tool in sustainable innovation, and subsequent competitive economic advantage. However, the number of apparently contradictory and inconclusive research results has increased in the past few years, indicating the need to introduce harmonized protocols and good practices in the nanosafety research community. Therefore, we aimed to evaluate if best-practice training and inter-laboratory comparison (ILC) of performance of the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay for the cytotoxicity assessment of nanomaterials among 15 European laboratories can improve quality in nanosafety testing. We used two well-described model nanoparticles, 40-nm carboxylated polystyrene (PS-COOH) and 50-nm amino-modified polystyrene (PS-NH2). We followed a tiered approach using well-developed standard operating procedures (SOPs) and sharing the same cells, serum and nanoparticles. We started with determination of the cell growth rate (tier 1), followed by a method transfer phase, in which all laboratories performed the first ILC on the MTS assay (tier 2). Based on the outcome of tier 2 and a survey of laboratory practices, specific training was organized, and the MTS assay SOP was refined. This led to largely improved intra- and inter-laboratory reproducibility in tier 3. In addition, we confirmed that PS-COOH and PS-NH2 are suitable negative and positive control nanoparticles, respectively, to evaluate impact of nanomaterials on cell viability using the MTS assay. Overall, we have demonstrated that the tiered process followed here, with the use of SOPs and representative control nanomaterials, is necessary and makes it possible to achieve good inter-laboratory reproducibility, and therefore high-quality nanotoxicological data.
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http://dx.doi.org/10.3390/nano10081430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466672PMC
July 2020

Long-term developmental effect of withholding parenteral nutrition in paediatric intensive care units: a 4-year follow-up of the PEPaNIC randomised controlled trial.

Lancet Child Adolesc Health 2020 07;4(7):503-514

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium. Electronic address:

Background: The PEPaNIC randomised controlled trial, which recruited 1440 critically ill infants and children in 2012-15, showed that withholding parenteral nutrition for 1 week (late-parenteral nutrition), compared with early supplementation within 24 h of admission to the paediatric intensive care unit (early-parenteral nutrition), prevented infections, accelerated recovery, and improved neurocognitive development assessed 2 years later. Because several neurocognitive domains can only be thoroughly assessed from age 4 years onwards, we aimed to determine the effect of late-parenteral nutrition versus early-parenteral nutrition on physical, neurocognitive, and emotional and behavioural development 4 years after randomisation.

Methods: This is a preplanned, blinded, 4-year follow-up study of participants included in the PEPaNIC trial (done at University Hospitals Leuven, Belgium; Erasmus Medical Centre Sophia Children's Hospital, Rotterdam, Netherlands; and Stollery Children's Hospital, Edmonton, AB, Canada) and of matched healthy children. Studied outcomes were anthropometrics; health status; parent-reported or caregiver-reported executive functions, and emotional and behavioural problems; and clinical tests for intelligence, visual-motor integration, alertness, motor coordination, and memory. Through multivariable linear and logistic regression analyses, after imputation for missing values (≤30%) and adjustment for risk factors, we investigated the effect of early-parenteral nutrition versus late-parenteral nutrition. This trial is registered with ClinicalTrials.gov, NCT01536275.

Findings: Between March 8, 2016, and Nov 8, 2019, 684 children from the original PEPaNIC trial (356 from the late-parenteral nutrition group and 328 from the early-parenteral nutrition group) were assessed for neurocognitive development at 4-years follow-up. Compared with the control group (369 healthy children), children who had critical illness had lower height (β-estimate -2·11 [95% CI -3·15 to -1·06]; p<0·0001) and head circumference (-0·42 [-0·67 to -0·18]; p=0.00077); and worse health status (eg, hospital admission odds ratio 4·27 [95% CI 3·12 to 5·84]; p<0·0001), neurocognitive (eg, parent-reported or caregiver-reported total executive functioning β-estimate 3·57 [95% CI 1·95 to 5·18], p<0·0001; total intelligence quotient -7·35 [-9·31 to -5·39], p<0·0001), and parent-reported or caregiver-reported emotional and behavioural developmental outcomes (internalising 2·73 [1·19 to 4·28], p=0·00055; externalising 1·63 [0·19 to 3·08], p=0·027; and total behavioural problems 2·95 [1·44 to 4·46], p=0·00013), adjusted for risk factors. Outcomes were never worse in the late-parenteral nutrition group compared with the early-parenteral nutrition group, but patients in the late-parenteral nutrition group had fewer parent-reported or caregiver-reported internalising (β-estimate -1·88 [95% CI -3·69 to -0·07]; p=0·042), externalising (-1·73 [-3·43 to -0·03]; p=0·046), and total emotional and behavioural problems (-2·44 [-4·22 to -0·67]; p=0·0070) than patients who had received early-parenteral nutrition, after adjusting for risk factors, and were no longer different from healthy controls for these outcomes.

Interpretation: Omitting early parenteral nutrition use for critically ill children did not adversely affect long-term outcomes 4 years after randomisation and protected against emotional and behavioural problems, further supporting the deimplementation of early parenteral nutrition.

Funding: European Research Council, Methusalem, Flanders Institute for Science and Technology, Research Foundation Flanders, Sophia Foundation, Stichting Agis Zorginnovatie, Erasmus Trustfonds, and the European Society for Clinical Nutrition and Metabolism.
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http://dx.doi.org/10.1016/S2352-4642(20)30104-8DOI Listing
July 2020

Social Processes: What Determines Industrial Workers' Intention to Use Exoskeletons?

Hum Factors 2020 05 23;62(3):337-350. Epub 2020 Jan 23.

70493 70497 Vrije Universiteit Brussel, Belgium.

Objective: The aim of this study is to test the unified theory of acceptance and use of technology (UTAUT) model for explaining the intention to use exoskeletons among industrial workers.

Background: Exoskeletons could help reduce physical workload and risk for injuries among industrial workers. Therefore, it is crucial to understand which factors play a role in workers' intention to use such exoskeletons.

Method: Industrial workers ( = 124) completed a survey on their attitudes regarding the use of exoskeletons at their workplace. Using partial least squares (PLS) path modeling, the UTAUT model and a revised version of the UTAUT model were fitted to these data.

Results: The adapted UTAUT model of Dwivedi et al. (2017) was able to explain up to 75.6% of the variance in intention to use exoskeletons, suggesting a reasonable model fit.

Conclusion: The model fit suggests that effort expectancy (how easy it seems to use an exoskeleton) plays an important role in predicting the intention to use exoskeletons. Social influence (whether others think workers should use exoskeletons) and performance expectancy (how useful exoskeletons seem to be for work) play a smaller role in predicting the intention to use.

Applications: This research informs companies about the optimal implementation of exoskeletons by improving the determinants of acceptance among their workers.
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http://dx.doi.org/10.1177/0018720819889534DOI Listing
May 2020

Nonthyroidal Illness Syndrome Across the Ages.

J Endocr Soc 2019 Dec 16;3(12):2313-2325. Epub 2019 Oct 16.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University Hospital, Leuven, Belgium.

In conditions of acute illness, patients present with reduced plasma T3 concentrations without a concomitant rise in TSH. In contrast, plasma concentrations of the inactive hormone rT3 increase, whereas plasma concentrations of T4 remain low-normal. This constellation of changes, referred to as nonthyroidal illness syndrome (NTIS), is present across all ages, from preterm neonates and over-term critically ill infants and children to critically ill adults. Although the severity of illness strongly correlates with the severity of the NTIS phenotype, the causality of this association remains debated, and pathophysiological mechanisms remain incompletely understood. In the acute phase of illness, NTIS appears to be caused predominantly by an increased peripheral inactivation of thyroid hormones, in which reduced nutritional intake plays a role. Current evidence suggests that these acute peripheral changes are part of a beneficial adaptation of the body to reduce expenditure of energy and to activate the innate immune response, which is important for survival. In contrast, in more severely ill and prolonged critically ill patients, an additional central suppression of the thyroid hormone axis alters and further aggravates the NTIS phenotype. Recent studies suggest that this central suppression may not be adaptive. Whether treatment of this central component of NTIS in prolonged critically ill patients, with the use of hypothalamic releasing factors, improves outcome remains to be investigated in large randomized control trials.
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http://dx.doi.org/10.1210/js.2019-00325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853682PMC
December 2019

Dynamics and prognostic value of the hypothalamus-pituitary-adrenal axis responses to pediatric critical illness and association with corticosteroid treatment: a prospective observational study.

Intensive Care Med 2020 01 11;46(1):70-81. Epub 2019 Nov 11.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Purpose: Increased systemic cortisol availability during adult critical illness is determined by reduced binding-proteins and suppressed breakdown rather than elevated ACTH. Dynamics, drivers and prognostic value of hypercortisolism during pediatric critical illness remain scarcely investigated.

Methods: This preplanned secondary analysis of the PEPaNIC-RCT (N = 1440), after excluding 420 children treated with corticosteroids before PICU-admission, documented (a) plasma ACTH, (free)cortisol and cortisol-metabolism at PICU-admission, day-3 and last PICU-day, their prognostic value, and impact of withholding early parenteral nutrition (PN), (b) the association between corticosteroid-treatment and these hormones, and (c) the association between corticosteroid-treatment and outcome.

Results: ACTH was normal upon PICU-admission and low thereafter (p ≤ 0.0004). Total and free cortisol were only elevated upon PICU-admission (p ≤ 0.0003) and thereafter became normal despite low binding-proteins (p < 0.0001) and persistently suppressed cortisol-metabolism (p ≤ 0.03). Withholding early-PN did not affect this phenotype. On PICU-day-3, high free cortisol and low ACTH independently predicted worse outcome (p ≤ 0.003). Also, corticosteroid-treatment initiated in PICU, which further suppressed ACTH (p < 0.0001), was independently associated with poor outcomes (earlier live PICU-discharge: p < 0.0001, 90-day mortality: p = 0.02).

Conclusion: In critically ill children, systemic cortisol availability is elevated only transiently, much lower than in adults, and not driven by elevated ACTH. Further ACTH lowering by corticosteroid-treatment indicates active feedback inhibition at pituitary level. Beyond PICU-admission-day, low ACTH and high cortisol, and corticosteroid-treatment, predicted poor outcome. This suggests that exogenously increasing cortisol availability during acute critical illness in children may be inappropriate. Future studies on corticosteroid-treatment in critically ill children should plan safety analyses, as harm may be possible.
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http://dx.doi.org/10.1007/s00134-019-05854-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954148PMC
January 2020

Xenopus laevis as a Bioindicator of Endocrine Disruptors in the Region of Central Chile.

Arch Environ Contam Toxicol 2019 Oct 17;77(3):390-408. Epub 2019 Aug 17.

Departamento de Ecología y Biodiversidad, Facultad Ciencias de la Vida, Universidad Andres Bello, República 440, Santiago, Chile.

One of the direct causes of biodiversity loss is environmental pollution resulting from the use of chemicals. Different kinds of chemicals, such as persistent organic pollutants and some heavy metals, can be endocrine disruptors, which act at low doses over a long period of time and have a negative effect on the reproductive and thyroid system in vertebrates worldwide. Research on the effects of endocrine disruptors and the use of bioindicators in neotropical ecosystems where pressure on biodiversity is high is scarce. In Chile, although endocrine disruptors have been detected at different concentrations in the environments of some ecosystems, few studies have been performed on their biological effects in the field. In this work, Xenopus laevis (African clawed frog), an introduced species, is used as a bioindicator for the presence of endocrine disruptors in aquatic systems with different degrees of contamination in a Mediterranean zone in central Chile. For the first time for Chile, alterations are described that can be linked to exposure to endocrine disruptors, such as vitellogenin induction, decreased testosterone in male frogs, and histological changes in gonads. Dioxin-like and oestrogenic activity was detected in sediments at locations where it seem to be related to alterations found in the frogs. In addition, an analysis of land use/cover use revealed that urban soil was the best model to explain the variations in frog health indicators. This study points to the usefulness of an invasive species as a bioindicator for the presence of endocrine-disruptive chemicals.
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http://dx.doi.org/10.1007/s00244-019-00661-6DOI Listing
October 2019

Nonthyroidal illness in critically ill children.

Curr Opin Endocrinol Diabetes Obes 2019 10;26(5):241-249

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University Hospital, Leuven, Belgium.

Purpose Of Review: This review summarizes recent literature on nonthyroidal illness syndrome (NTI) and outcome of pediatric critical illness, to provide insight in pathophysiology and therapeutic implications.

Recent Findings: NTI is typically characterized by lowered triiodothyronine levels without compensatory TSH rise. Although NTI severity is associated with poor outcome of pediatric critical illness, it remains unclear whether this association reflects an adaptive protective response or contributes to poor outcome. Recently, two metabolic interventions that improved outcome also altered NTI in critically ill children. These studies shed new light on the topic, as the results suggested that the peripheral NTI component, with inactivation of thyroid hormone, may represent a beneficial adaptation, whereas the central component, with suppressed TSH-driven thyroid hormone secretion, may be maladaptive. There is currently insufficient evidence for treatment of NTI in children. However, the recent findings raised the hypothesis that reactivation of the central NTI component could offer benefit, which should be tested in RCTs.

Summary: NTI in critically ill children can be modified by metabolic interventions. The peripheral, but not the central, component of NTI may be a beneficial adaptive response. These findings open perspectives for the development of novel strategies to improve outcome of critical illness in children.
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http://dx.doi.org/10.1097/MED.0000000000000494DOI Listing
October 2019

Early Supplemental Parenteral Nutrition in Critically Ill Children: An Update.

J Clin Med 2019 Jun 11;8(6). Epub 2019 Jun 11.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University Hospital, 3000 Leuven, Belgium.

In critically ill children admitted to pediatric intensive care units (PICUs), enteral nutrition (EN) is often delayed due to gastrointestinal dysfunction or interrupted. Since a macronutrient deficit in these patients has been associated with adverse outcomes in observational studies, supplemental parenteral nutrition (PN) in PICUs has long been widely advised to meeting nutritional requirements. However, uncertainty of timing of initiation, optimal dose and composition of PN has led to a wide variation in previous guidelines and current clinical practices. The PEPaNIC (Early versus Late Parenteral Nutrition in the Pediatric ICU) randomized controlled trial recently showed that withholding PN in the first week in PICUs reduced incidence of new infections and accelerated recovery as compared with providing supplemental PN early (within 24 hours after PICU admission), irrespective of diagnosis, severity of illness, risk of malnutrition or age. The early withholding of amino acids in particular, which are powerful suppressors of intracellular quality control by autophagy, statistically explained this outcome benefit. Importantly, two years after PICU admission, not providing supplemental PN early in PICUs did not negatively affect mortality, growth or health status, and significantly improved neurocognitive development. These findings have an important impact on the recently issued guidelines for PN administration to critically ill children. In this review, we summarize the most recent literature that provides evidence on the implications for clinical practice with regard to the use of early supplemental PN in critically ill children.
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http://dx.doi.org/10.3390/jcm8060830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616588PMC
June 2019

International survey of De-implementation of initiating parenteral nutrition early in Paediatric intensive care units.

BMC Health Serv Res 2019 Jun 13;19(1):379. Epub 2019 Jun 13.

Department of Paediatrics and Paediatric Surgery, Erasmus MC - Sophia Children's Hospital, University Medical Centre Rotterdam, Wytemaweg 80, 3015, CN, Rotterdam, The Netherlands.

Background: Initiating parenteral nutrition (PN) within 24 h in critically ill children is inferior to withholding PN during the first week, as was found in the PEPaNIC study. The aims of this study were to investigate de-implementation of early initiation of PN at PICUs worldwide, and to identify factors influencing de-implementation.

Methods: A cross-sectional online survey was conducted (May - October 2017), consisting of 41 questions addressing current PN practices, the degree of de-implementation, and factors affecting de-implementation.

Results: We analysed 81 responses from 39 countries. Of these 81 respondents, 53 (65%) were aware of the findings of the PEPaNIC study, and 43 (53%) have read the article. In these 43 PICUs, PN was completely withheld during the first week in 10 PICUs, of which 5 already withheld PN (12%), and 5 de-implemented early initiation of PN (12%). Partial de-implementation was reported by 17 (40%) and no de-implementation by 16 (37%). Higher de-implementation rates were observed when the interpreted level of evidence and grade of recommendation of PEPaNIC was high. Predominant reasons for retaining early initiation of PN were concerns on withholding amino acids, the safety in undernourished children and neonates, and the long-term consequences. Furthermore, the respondents were waiting for updated guidelines.

Conclusions: One year after the publication of the PEPaNIC trial, only two-thirds of the respondents was aware of the study results. Within this group, early initiation of PN was de-implemented completely in 12% of the PICUs, while 40% asserted partial de-implementation. Increasing the awareness, addressing the intervention-specific questions and more frequently revising international guidelines might help to accelerate de-implementation of ineffective, unproven or harmful healthcare.
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http://dx.doi.org/10.1186/s12913-019-4223-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567488PMC
June 2019

Role of nanoparticle size and sialic acids in the distinct time-evolution profiles of nanoparticle uptake in hematopoietic progenitor cells and monocytes.

J Nanobiotechnology 2019 May 13;17(1):62. Epub 2019 May 13.

Health Department, Flemish Institute For Technological Research (VITO), Boeretang 200, 2400, Mol, Belgium.

Background: Human hematopoietic progenitor cells (HPCs) are important for cell therapy in cancer and tissue regeneration. In vitro studies have shown a transient association of 40 nm polystyrene nanoparticles (PS NPs) with these cells, which is of interest for intelligent design and application of NPs in HPC-based regenerative protocols. In this study, we aimed to investigate the involvement of nanoparticles' size and membrane-attached glycan molecules in the interaction of HPCs with PS NPs, and compared it with monocytes. Human cord blood-derived HPCs and THP-1 cells were exposed to fluorescently labelled, carboxylated PS NPs of 40, 100 and 200 nm. Time-dependent nanoparticle membrane association and/or uptake was observed by measuring fluorescence intensity of exposed cells at short time intervals using flow cytometry. By pretreating the cells with neuraminidase, we studied the possible effect of membrane-associated sialic acids in the interaction with NPs. Confocal microscopy was used to visualize the cell-specific character of the NP association.

Results: Confocal images revealed that the majority of PS NPs was initially observed to be retained at the outer membrane of HPCs, while the same NPs showed immediate internalization by THP-1 monocytic cells. After prolonged exposure up to 4 h, PS NPs were also observed to enter the HPCs' intracellular compartment. Cell-specific time courses of NP association with HPCs and THP-1 cells remained persistent after cells were enzymatically treated with neuraminidase, but significantly increased levels of NP association could be observed, suggesting a role for membrane-associated sialic acids in this process.

Conclusions: We conclude that the terminal membrane-associated sialic acids contribute to the NP retention at the outer cell membrane of HPCs. This retention behavior is a unique characteristic of the HPCs and is independent of NP size.
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http://dx.doi.org/10.1186/s12951-019-0495-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513515PMC
May 2019

Non-Thyroidal Illness Syndrome in Critically Ill Children: Prognostic Value and Impact of Nutritional Management.

Thyroid 2019 04 11;29(4):480-492. Epub 2019 Mar 11.

1 Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University Hospital, Leuven, Belgium.

Introduction: Non-thyroidal illness (NTI), which occurs with fasting and in response to illness, is characterized by thyroid hormone inactivation with low triiodothyronine (T3) and high reverse T3 (rT3), followed by suppressed thyrotropin (TSH). Withholding supplemental parenteral nutrition early in pediatric critical illness (late-PN), thus accepting low/no macronutrient intake up to day 8 in the pediatric intensive care unit (PICU), accelerated recovery compared to initiating supplemental parenteral nutrition early (early-PN). Whether NTI is harmful or beneficial in pediatric critical illness and how it is affected by a macronutrient deficit remains unclear. This study investigated the prognostic value of NTI, the impact of late-PN on NTI, and whether such impact explains or counteracts the outcome benefit of late-PN in critically ill children.

Methods: This preplanned secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit randomized controlled trial quantified serum TSH, total thyroxine (T4), T3, and rT3 concentrations in 982 patients upon PICU admission versus 64 matched healthy children and in 772 propensity score-matched early-PN and late-PN patients upon admission and at day 3 or last PICU day for shorter PICU stay. Associations between thyroid hormone concentrations upon admission and outcome, as well as impact of late-PN on NTI in relation with outcome, were assessed with univariable analyses and multivariable logistic regression, linear regression, or Cox proportional hazard analysis, adjusted for baseline risk factors.

Results: Upon PICU admission, critically ill children revealed lower TSH, T4, T3, and T3/rT3 and higher rT3 than healthy children (p < 0.0001). A more pronounced NTI upon admission, with low T4, T3, and T3/rT3 and high rT3 was associated with higher mortality and morbidity. Late-PN further reduced T4, T3, and T3/rT3 and increased rT3 (p ≤ 0.001). Statistically, the further lowering of T4 by late-PN reduced the outcome benefit (p < 0.0001), whereas the further lowering of T3/rT3 explained part of the outcome benefit of late-PN (p ≤ 0.004). This effect was greater for infants than for older children.

Conclusion: In critically ill children, the peripheral inactivation of thyroid hormone, characterized by a decrease in T3/rT3, which is further accentuated by low/no macronutrient intake, appears beneficial. In contrast, the central component of NTI attributable to suppressed TSH, evidenced by the decrease in T4, seems to be a harmful response to critical illness. Whether treating the central component with TSH releasing hormone infusion in the PICU is beneficial requires further investigation.
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http://dx.doi.org/10.1089/thy.2018.0420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457888PMC
April 2019

Molecular drug susceptibility testing and strain typing of tuberculosis by DNA hybridization.

PLoS One 2019 7;14(2):e0212064. Epub 2019 Feb 7.

Flemish Institute for Technological Research, VITO, Mol, Belgium.

In Mycobacterium tuberculosis (Mtb) the detection of single nucleotide polymorphisms (SNPs) is of high importance both for diagnostics, since drug resistance is primarily caused by the acquisition of SNPs in multiple drug targets, and for epidemiological studies in which strain typing is performed by SNP identification. To provide the necessary coverage of clinically relevant resistance profiles and strain types, nucleic acid-based measurement techniques must be able to detect a large number of potential SNPs. Since the Mtb problem is pressing in many resource-poor countries, requiring low-cost point-of-care biosensors, this is a non-trivial technological challenge. This paper presents a proof-of-concept in which we chose simple DNA-DNA hybridization as a sensing principle since this can be transferred to existing low-cost hardware platforms, and we pushed the multiplex boundaries of it. With a custom designed probe set and a physicochemical-driven data analysis it was possible to simultaneously detect the presence of SNPs associated with first- and second-line drug resistance and Mtb strain typing. We have demonstrated its use for the identification of drug resistance and strain type from a panel of phylogenetically diverse clinical strains. Furthermore, reliable detection of the presence of a minority population (<5%) of drug-resistant Mtb was possible.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212064PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366778PMC
November 2019

Performance of Pediatric Mortality Prediction Scores for PICU Mortality and 90-Day Mortality.

Pediatr Crit Care Med 2019 02;20(2):113-119

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University Hospital, Leuven, Belgium.

Objectives: The use of mortality prediction scores in clinical trials in the PICU is essential for comparing patient groups. Because of the decline in PICU mortality over the last decades, leading to a shift toward later deaths, recent trials use 90-day mortality as primary outcome for estimating mortality and survival more accurately. This study assessed and compared the performance of two frequently used PICU mortality prediction scores for prediction of PICU and 90-day mortality.

Design: This secondary analysis of the randomized controlled Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit trial compared the discrimination (area under the receiver operating characteristic curve) and calibration of the Pediatric Index of Mortality 3 and the Pediatric Risk of Mortality III scores for prediction of PICU and 90-day mortality.

Setting: Three participating PICUs within academic hospitals in Belgium, the Netherlands, and Canada.

Patients: One-thousand four-hundred twenty-eight critically ill patients 0-17 years old.

Interventions: None.

Measurements And Main Results: Although Pediatric Index of Mortality 3 only includes information available at the time of PICU admission, thus before any intervention in the PICU, it showed good discrimination (area under the receiver operating characteristic curve, 0.894; 95% CI, 0.892-0.896) and good calibration (no deviation from the diagonal, p = 0.58) for PICU mortality. Pediatric Risk of Mortality III, which involves the worst values for the evaluated variables during the first 24 hours of PICU stay, was statistically more discriminant (area under the receiver operating characteristic curve, 0.920; 95% CI, 0.918-0.921; p = 0.04) but poor in calibration (significant deviation from the diagonal; p = 0.04). Pediatric Index of Mortality 3 and Pediatric Risk of Mortality III discriminated equally well between 90-day mortality and survival (area under the receiver operating characteristic curve, 0.867; 95% CI, 0.866-0.869 and area under the receiver operating characteristic curve, 0.882; 95% CI, 0.880-0.884, respectively, p = 0.77), but Pediatric Risk of Mortality III was not well calibrated (p = 0.04), unlike Pediatric Index of Mortality 3 (p = 0.34).

Conclusions: Pediatric Index of Mortality 3 performed better in calibration for predicting PICU and 90-day mortality than Pediatric Risk of Mortality III and is not influenced by intervention or PICU quality of care. Therefore, Pediatric Index of Mortality 3 seems a better choice for use in clinical trials with 90-day mortality as primary outcome.
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http://dx.doi.org/10.1097/PCC.0000000000001764DOI Listing
February 2019

Phthalate and alternative plasticizers in indwelling medical devices in pediatric intensive care units.

J Hazard Mater 2019 02 1;363:64-72. Epub 2018 Oct 1.

Toxicological Centre, University of Antwerp, Wilrijk, Belgium. Electronic address:

The present study aimed to identify plasticizers present in indwelling plastic medical devices commonly used in the pediatric intensive care unit (PICU). We have analyzed a wide range of medical devices (n = 97) daily used in the PICUs of two academic hospitals in Belgium and the Netherlands. Identified compounds varied between the samples. Most of the indwelling medical devices and essential accessories were found to actively leach phthalates and alternative plasticizers. Results indicated that DEHP was predominantly present as plasticizer (60 of 97 samples), followed by bis(2-ethylhexyl) adipate (DEHA, 32 of 97), bis(2-ethylhexyl) terephthalate (DEHT, 24 of 97), tris(2-ethylhexyl) trimellitate (TOTM, 20 of 97), and tributyl-O-acetyl citrate (ATBC, 10 of 97). Other plasticizers, such as di-isononyl-cyclohexane-1,2-dicarboxylate (DINCH, 2 of 97), di-isononyl phthalate (DiNP, 4 of 97), di(2-propylheptyl) phthalate (DPHP, 4 of 97) and di-isodecyl phthalate (DiDP, 2 of 97) were detected in < 5% of the investigated samples. Several devices contained multiple plasticizers, e.g. devices containing TOTM contained also DEHP and DEHT. Our data indicate that PICU patients are exposed to a wide range of plasticizers, including the controversial DEHP. Future studies should investigate the exposure to APs in children staying in the PICU and the possible health effects thereof.
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http://dx.doi.org/10.1016/j.jhazmat.2018.09.087DOI Listing
February 2019

Long-term developmental effects of withholding parenteral nutrition for 1 week in the paediatric intensive care unit: a 2-year follow-up of the PEPaNIC international, randomised, controlled trial.

Lancet Respir Med 2019 02 14;7(2):141-153. Epub 2018 Sep 14.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. Electronic address:

Background: The paediatric early versus late parenteral nutrition in critical illness (PEPaNIC) multicentre, randomised, controlled trial showed that, compared with early parenteral nutrition, withholding supplemental parenteral nutrition for 1 week in the paediatric intensive care unit (PICU; late parenteral nutrition) reduced infections and accelerated recovery from critical illness in children. We aimed to investigate the long-term impact on physical and neurocognitive development of early versus late parenteral nutrition.

Methods: In this preplanned 2-year follow-up study, all patients included in the PEPaNIC trial (which was done in University Hospitals Leuven, Belgium; Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, Netherlands; and Stollery Children's Hospital, Edmonton, AB, Canada) were approached for possible assessment of physical and neurocognitive development compared with healthy children who were matched for age and sex, and who had never been admitted to a neonatal ICU or a PICU. Assessed outcomes comprised anthropometric data; health status; parent-reported or caregiver-reported executive functions and emotional and behavioural problems; and tests for intelligence, visual-motor integration, alertness, motor coordination, inhibitory control, cognitive flexibility, and memory. To address partial responses among the children tested, we did multiple data imputation by chained equations before univariable and multivariable linear and logistic regression analyses adjusted for risk factors. This trial is registered with ClinicalTrials.gov, number NCT01536275.

Findings: At the 2-year follow-up, 60 (8%) of 717 children who received late parenteral nutrition and 63 (9%) of 723 children who received early parenteral nutrition had died (p=0·81). 68 (9%) of 717 children who received late and 91 (13%) of 723 children who received early parenteral nutrition were too disabled for neurocognitive assessment (p=0·059), and 786 patients (395 assigned to late and 391 assigned to early parenteral nutrition) consented for testing. 786 patients and 405 healthy control children underwent long-term outcome testing between Aug 4, 2014, and Jan 19, 2018, and were included in the imputation model for subsequent multivariable analyses. Late parenteral nutrition did not adversely affect anthropometric data, health status, or neurological functioning, and improved parent-reported or caregiver-reported executive functioning (late vs early parenteral nutrition β estimate -2·258, 95% CI -4·012 to -0·504; p=0·011), more specifically inhibition (-3·422, -5·171 to -1·673; p=0·0001), working memory (-2·016, -3·761 to -0·270; p=0·023), and meta-cognition (-1·957, -3·694 to -0·220; p=0·027). Externalising behavioural problems (β estimate -1·715, 95% CI -3·325 to -0·106; p=0·036) and visual-motor integration (0·468, 0·087 to 0·850; p=0·016) were also improved in the late parenteral nutrition group compared with the early parenteral nutrition group. After Bonferroni correction for multiple comparisons, the effect on inhibitory control remained significant (p=0·0001).

Interpretation: Withholding early parenteral nutrition for 1 week in the PICU did not negatively affect survival, anthropometrics, health status, and neurocognitive development, and improved inhibitory control 2 years after PICU admission.

Funding: European Research Council Advanced Grant, Methusalem programme provided by the Flemish Government, Flemish Agency for Innovation by Science and Technology (IWT), Research Foundation Flanders (FWO), Sophia Children's Hospital Foundation (SSWO), Stichting Agis Zorginnovatie, Erasmus Trustfonds, and European Society for Parenteral and Enteral Nutrition (ESPEN) research grant.
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http://dx.doi.org/10.1016/S2213-2600(18)30334-5DOI Listing
February 2019

Ultrafiltration and size exclusion chromatography combined with asymmetrical-flow field-flow fractionation for the isolation and characterisation of extracellular vesicles from urine.

J Extracell Vesicles 2018 3;7(1):1490143. Epub 2018 Jul 3.

Sustainable Health Department, Flemish Institute for Technological Research (VITO), Mol, Belgium.

Extracellular vesicles (EVs) have a great potential in clinical applications. However, their isolation from different bodily fluids and their characterisation are currently not optimal or standardised. Here, we report the results of examining the performance of ultrafiltration combined with size exclusion chromatography (UF-SEC) to isolate EVs from urine. The results reveal that UF-SEC is an efficient method and provides high purity. Furthermore, we introduce asymmetrical-flow field-flow fractionation coupled with a UV detector and multi-angle light-scattering detector (AF4/UV-MALS) as a characterisation method and compare it with current methods. We demonstrate that AF4/UV-MALS is a straightforward and reproducible method for determining size, amount and purity of isolated urinary EVs.
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http://dx.doi.org/10.1080/20013078.2018.1490143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032024PMC
July 2018

The comet assay in human biomonitoring: cryopreservation of whole blood and comparison with isolated mononuclear cells.

Mutagenesis 2018 02;33(1):41-47

Health Unit, Flemish Institute for Technological Research (VITO), Belgium.

The comet assay is often applied in human biomonitoring. Most of the time the assay is performed with isolated peripheral blood mononuclear cells (PBMC). However, using whole blood instead of isolated cells reduces processing time, and only 20 µl is sufficient for analysis. In this study, a cryopreservation protocol for human whole blood for application in the comet assay was optimised by removing excess plasma before adding freezing medium. Cryopreservation of whole blood samples (n = 30) did not increase the detected level of strand breaks and formamidopyrimidine DNA glycosylase (FPG)-sensitive sites. Although there was no significant correlation with breaks measured in fresh whole blood, strand breaks detected in frozen whole blood were significantly correlated with breaks measured in frozen PBMC (Pearson correlation r = 0.54, P < 0.01). This correlation was however not observed for FPG-sensitive sites. Since we do not yet know the full extent to which cryopreservation might influence the blood cell population, care should be taken to ensure a similar cell type and storage conditions for all samples in one study.
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http://dx.doi.org/10.1093/mutage/gex034DOI Listing
February 2018

Perceptions and Use of Technology to Support Older Adults with Multimorbidity.

Stud Health Technol Inform 2017 ;242:160-167

Trinity Centre for Practice and Healthcare Innovation, School of Nursing and Midwifery, Trinity College Dublin, Ireland.

Digital technologies hold great potential to improve and advance home based integrated care for older people living with multiple chronic health conditions. In this paper, we present the results of a user requirement study for a planned digital integrated care system, based on the experiences and needs of key stakeholders. We present rich, multi-stakeholder, qualitative data on the perceptions and use of technology among older people with multiple chronic health conditions and their key support actors. We have outlined our future work for the design of the system, which will involve continuous stakeholder engagement through a user-centred co-design method.
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April 2018

Thermodynamic framework to assess low abundance DNA mutation detection by hybridization.

PLoS One 2017 25;12(5):e0177384. Epub 2017 May 25.

Flemish Institute for Technological Research, VITO, Mol, Belgium.

The knowledge of genomic DNA variations in patient samples has a high and increasing value for human diagnostics in its broadest sense. Although many methods and sensors to detect or quantify these variations are available or under development, the number of underlying physico-chemical detection principles is limited. One of these principles is the hybridization of sample target DNA versus nucleic acid probes. We introduce a novel thermodynamics approach and develop a framework to exploit the specific detection capabilities of nucleic acid hybridization, using generic principles applicable to any platform. As a case study, we detect point mutations in the KRAS oncogene on a microarray platform. For the given platform and hybridization conditions, we demonstrate the multiplex detection capability of hybridization and assess the detection limit using thermodynamic considerations; DNA containing point mutations in a background of wild type sequences can be identified down to at least 1% relative concentration. In order to show the clinical relevance, the detection capabilities are confirmed on challenging formalin-fixed paraffin-embedded clinical tumor samples. This enzyme-free detection framework contains the accuracy and efficiency to screen for hundreds of mutations in a single run with many potential applications in molecular diagnostics and the field of personalised medicine.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177384PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444680PMC
September 2017

A Novel Exposure System Termed NAVETTA for In Vitro Laminar Flow Electrodeposition of Nanoaerosol and Evaluation of Immune Effects in Human Lung Reporter Cells.

Environ Sci Technol 2017 May 14;51(9):5259-5269. Epub 2017 Apr 14.

Paris Lodron University of Salzburg (PLUS) , Department of Molecular Biology, Hellbrunnerstrasse 34, 5020 Salzburg, Austria.

A new prototype air-liquid interface (ALI) exposure system, a flatbed aerosol exposure chamber termed NAVETTA, was developed to investigate deposition of engineered nanoparticles (NPs) on cultured human lung A549 cells directly from the gas phase. This device mimics human lung cell exposure to NPs due to a low horizontal gas flow combined with cells exposed at the ALI. Electrostatic field assistance is applied to improve NP deposition efficiency. As proof-of-principle, cell viability and immune responses after short-term exposure to nanocopper oxide (CuO)-aerosol were determined. We found that, due to the laminar aerosol flow and a specific orientation of inverted transwells, much higher deposition rates were obtained compared to the normal ALI setup. Cellular responses were monitored with postexposure incubation in submerged conditions, revealing CuO dissolution in a concentration-dependent manner. Cytotoxicity was the result of ionic and nonionic Cu fractions. Using the optimized inverted ALI/postincubation procedure, pro-inflammatory immune responses, in terms of interleukin (IL)-8 promoter and nuclear factor kappa B (NFκB) activity, were observed within short time, i.e. One hour exposure to ALI-deposited CuO-NPs and 2.5 h postincubation. NAVETTA is a novel option for mimicking human lung cell exposure to NPs, complementing existing ALI systems.
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http://dx.doi.org/10.1021/acs.est.7b00493DOI Listing
May 2017