bluuebunny/crossref_metadata_2025 huggingface dataset:
Rethinking Resilience Analytics
Authors: Eisenberg Daniel , Seager Thomas , Alderson David L.
Published: May 2019

The concept of “resilience analytics” has recently been proposed as a means to leverage the promise of big data to improve the resilience of interdependent critical infrastructure systems and the communities supported by them. Given recent advances in machine learning and other data‐driven analytic techniques, as well as the prevalence of high‐profile natural and man‐made disasters, the temptation to pursue resilience analytics without question is almost overwhelming. Indeed, we find big data analytics capable to support resilience to rare, situational surprises captured in analytic models. Nonetheless, this article examines the efficacy of resilience analytics by answering a single motivating question: Can big data analytics help cyber–physical–social (CPS) systems adapt to surprise? This article explains the limitations of resilience analytics when critical infrastructure systems are challenged by fundamental surprises never conceived during model development. In these cases, adoption of resilience analytics may prove either useless for decision support or harmful by increasing dangers during unprecedented events. We demonstrate that these dangers are not limited to a single CPS context by highlighting the limits of analytic models during hurricanes, dam failures, blackouts, and stock market crashes. We conclude that resilience analytics alone are not able to adapt to the very events that motivate their use and may, ironically, make CPS systems more vulnerable. We present avenues for future research to address this deficiency, with emphasis on improvisation to adapt CPS systems to fundamental surprise.
Eyberg Child Behavior Inventory (ECBI): Normative data, psychometric properties, and associations with socioeconomic status in Finnish children
Authors: Sorsa Johanna , Fontell Tuija , Laajasalo Taina , Aronen Eeva T.
Published: May 2019

Assessment of behavioral disorders is one of the most commonly encountered tasks in child psychiatry. The Eyberg Child Behavior Inventory (ECBI) is a widespread measurement tool used for assessing conduct problems, though the psychometric properties of the tool have varied in different samples. In this study, the ECBI was evaluated in a Finnish population based sample of children aged 4 to 12 years (n = 1,715). Factor structure and internal consistency of the ECBI and associates of behavioral problems in Finnish children were evaluated. The results showed that a unidimensional one‐factor solution for the ECBI intensity scale was the best fit for the data. The ECBI mean scores were considerably higher in our sample compared to other Nordic countries. Boys scored higher than girls on both ECBI scales, and the mean scores decreased with child's age. Socioeconomic status (SES) was weakly connected to the ECBI scores. Our results highlight the need for country specific reference norms in order to improve the clinical utility of evidence‐based measures for assessing conduct problems.
Preschoolers prefer in‐group to out‐group members, but equally condemn their immoral acts
Authors: Schuhmacher Nils , Kärtner Joscha
Published: May 2019

Previous research has shown that young children robustly display in‐group favoritism; that is, they favor in‐group over out‐group members. Moreover, preschoolers also consider information on morality in their evaluations of others. In the present study, we integrated both aspects: In particular, fifty‐six 4‐ to 6‐year‐old preschoolers were assigned to minimal groups and observed either prosocial or antisocial acts conducted by either an in‐group or an out‐group member. After observing these behaviors, children's liking and sharing were significantly higher for moral compared to immoral actors. In addition, children's liking and sharing were substantially higher for in‐group compared to out‐group actors. However, when children were directly asked to morally evaluate the actor's conduct, no in‐group favoritism emerged: In particular, children evaluated immoral acts conducted by an in‐group or an out‐group agent as equally bad/wrong and similarly claimed that these acts deserve punishment. These findings demonstrate that preschoolers differentially weigh information on group membership and moral valence depending on the type of evaluation, namely sharing and liking versus explicit moral evaluations of others’ conduct.
Results and reflections from the PROfiling Consortium on Antibody Repertoire and Effector functions in kidney transplantation: A mini‐review
Authors: Kamburova Elena G. , Hoitsma Andries , Claas Frans H. , Otten Henny G. ,   On behalf of the PROCARE Consortium
Published: May 2019

Kidney transplantation is the best treatment option for patients with end‐stage renal disease (ESRD). The waiting time for a deceased donor kidney in the Netherlands is approximately 3 years. Mortality among patients on the waiting list is high. The aim of the PROCARE consortium (PROfiling Consortium on Antibody Repertoire and Effector functions) was to decrease the waiting time by providing a matching algorithm yielding a prolonged graft survival and less HLA‐immunization compared with the currently used Eurotransplant Kidney allocation system. In this study, 6097 kidney transplants carried out between January 1995 and December 2005 were re‐examined with modern laboratory techniques and insights that were not available during that time period. In this way, we could identify potential new parameters that can be used to improve the matching algorithm and prolong graft survival. All eight University Medical Centers in the Netherlands participated in this multicenter study. To improve the matching algorithm, we used as central hypothesis that the combined presence of class‐I and ‐II single‐antigen bead (SAB)‐defined donor‐specific HLA antibodies (DSA) prior to transplantation, non‐HLA antibodies, the number of B‐ and/or T‐cell epitopes recognized on donor HLA, and specific polymorphisms in effector mechanisms of IgG were associated with an increased risk for graft failure. The purpose of this article is to relate the results obtained from the PROCARE consortium study to other studies published in recent years. The clinical relevance of SAB‐defined DSA, complement‐fixing DSA, non‐HLA antibodies, and the effector functions of (non)‐HLA‐antibodies will be discussed.
A novel HLA‐A*02 allele, A*02:828, identified by next‐generation sequencing in a Chinese individual
Authors: Wang Yan , Zhou Yunli
Published: May 2019

HLA‐A*02:828 differs from A*02:01:01:01 by a single non‐synonymous mutation in exon 2.
Surgical decompression, with or without adjunctive therapy, for palliative treatment of primary vertebral osteosarcoma in dogs
Authors: Dixon Alexandra , Chen Annie , Rossmeisl John H. , Sturges Beverly , Vernau Karen , Levine Jonathan M. , Otamendi Arturo , Early Peter , Partnow Alix , Curtis Lara , Thomovsky Stephanie , Packer Rebecca A. , Mauler Daniela A.
Published: May 2019

Vertebral osteosarcoma (OSA) is the most common primary vertebral tumor in dogs, however studies examining the survival time after surgical decompression of these tumors are limited. There is also limited information regarding the benefit of adjunctive treatments such as radiation therapy or chemotherapy in these patients. The goal of this study was to determine survival time of dogs with primary vertebral OSA after palliative decompressive surgery alone and combined with radiation therapy and/or chemotherapy. Records from 22 client‐owned dogs diagnosed with primary vertebral OSA and treated with decompressive surgery were collected retrospectively from eight referral institutions. Survival time was assessed for dogs treated with surgery alone as well as dogs who received adjunctive radiation therapy and/or chemotherapy. Median survival time in the 12 dogs treated with surgery alone was 42 days (range: 3‐1333 days). The three dogs treated with surgery and chemotherapy had a median survival time of 82 days (range: 56‐305 days). Only one dog was treated with surgery and radiation therapy; this dog survived 101 days. Six dogs were treated with surgery, radiation therapy and chemotherapy; these dogs had a median survival time of 261 days (range: 223‐653 days). Cause of death in all cases that survived the initial postoperative period was euthanasia secondary to confirmed or suspected tumor regrowth. The results of this study suggest that definitive radiation therapy, possibly combined with concurrent chemotherapy, significantly improves survival in dogs treated with palliative decompressive surgery for vertebral OSA and should be the treatment of choice in selected cases.
Hypofractionated radiotherapy in nine dogs with unresectable solitary lung adenocarcinoma
Authors: Kawabe Mifumi , Kitajima Yuka , Murakami Mami , Iwasaki Ryota , Goto Sho , Sakai Hiroki , Mori Takashi
Published: May 2019

Although lung lobectomy is the most common treatment option for dogs with solitary lung tumors, surgery often cannot be performed at the time of diagnosis. In this retrospective, case series study, we described the effects of hypofractionated radiotherapy for tumor mass reduction in nine dogs with solitary lung adenocarcinoma that were later considered for surgical resection, and we assessed the tolerability of the radiation protocol. Tumors were deemed unresectable by the attending veterinarian. The dose prescription was 7.0‐12.0 Gy/fraction in four to seven fractions, administered weekly for a total dose of 40‐50 Gy. Treatment planning prioritized normal tissue dose constraints. The median interval between the last radiotherapy session and maximum tumor size reduction was 56 (range: 26‐196) days, with six and three dogs exhibiting a partial response and stable disease, respectively. Although acute and late radiation‐induced toxicity to the skin and/or lungs developed in all nine dogs, it was self‐limiting or improved with short‐term anti‐inflammatory treatment. Tumor progression after initial size reduction was confirmed in three dogs at 62, 126, and 175 days, respectively, after the last radiotherapy session. Seven of the nine dogs underwent lobectomy a median of 68 days after radiotherapy when tumors were in partial response or stable disease or at the time of progression, and five received systemic chemotherapy concurrent with or after radiotherapy. These findings suggest that hypofractionated radiotherapy for canine solitary lung adenocarcinoma is useful when the tumor is large or when surgery cannot be performed immediately after diagnosis.
Evaluation of surgical models for training veterinary students to perform enterotomies
Authors: Grimes Janet A. , Wallace Mandy L. , Schmiedt Chad W. , Parks Andrew H.
Published: May 2019

Objective

To compare surgical models for teaching enterotomies to students.

Study design

Prospective, randomized study.

Sample population

Second‐year veterinary students (n = 59) and faculty surgeons/surgery residents (n = 19).

Methods

Participants performed an enterotomy on each of 3 models (equine cadaver intestine, SurgiReal small intestine simulator, and SynDaver canine bowel) and completed a survey comparing them to either an enterotomy on an anesthetized pig (students) or intestinal surgery experience (faculty/residents). Surveys results were compiled and analyzed.

Results

Both student and faculty/resident groups rated cadaver intestine as more similar to live intestine compared with the synthetic models for incision, tissue handling, mucosal eversion, needle passage, knot tying, and best preparing for live intestine. Students rated SynDaver as more similar to live intestine than SurgiReal for incision and ranked SurgiReal as more similar to live intestine than SynDaver for mucosal eversion. There was no difference between the ranks assigned to SurgiReal and SynDaver for faculty/residents. Faculty/residents responded most often that cadaver intestine would be the model they recommend for training students.

Conclusion

Cadaver intestine was the model most similar to live intestine for all variables tested. SurgiReal and SynDaver models were comparable to each other but did not simulate live intestine as well as cadaver intestine.

Clinical significance

Cadaver intestine more closely approximated live intestine compared with either synthetic model. SurgiReal and SynDaver may be adequate alternatives if cadaver intestine is unavailable.
Cardiovascular and respiratory profiles during the sleep–wake cycle of rats previously submitted to chronic intermittent hypoxia
Authors: Bazilio Darlan S. , Bonagamba Leni G. H. , Moraes Davi J. A. , Machado Benedito H.
Published: May 2019

New Findings

What is the central question of this study?

Chronic intermittent hypoxia (CIH) causes increased arterial pressure (AP), sympathetic overactivity and changes in expiratory modulation of sympathetic activity. However, changes in the short‐term sleep–wake cycle pattern after CIH and their potential impact on cardiorespiratory parameters have not been reported previously.

What is the main finding and its importance?

Exposure to CIH for 10 days elevates AP in wakefulness and sleep but does not cause major changes in short‐term sleep–wake cycle pattern. A higher incidence of muscular expiratory activity was observed in rats exposed to CIH only during wakefulness, indicating that active expiration is not required for the increase in AP in rats submitted to CIH.

Chronic intermittent hypoxia (CIH) increases arterial pressure (AP) and changes sympathetic–respiratory coupling. However, the alterations in the sleep–wake cycle after CIH and their potential impact on cardiorespiratory parameters remain unknown. Here, we evaluated whether CIH‐exposed rats present changes in their short‐term sleep–wake cycle pattern and in cardiorespiratory parameters. Male Wistar rats (∼250 g) were divided into CIH and control groups. The CIH rats were exposed to 8 h day−1 of cycles of normoxia (fraction of inspired O2 = 0.208, 5 min) followed by hypoxia (fraction of inspired O2 = 0.06, 30–40 s) for 10 days. One day after CIH, electrocorticographic activity, cervical EMG, AP and heart rate were recorded for 3 h. Plethysmographic recordings were collected for 2 h. A subgroup of control and CIH rats also had the diaphragm and oblique abdominal muscle activities recorded. Chronic intermittent hypoxia did not alter the time for sleep onset, total time awake, durations of rapid eye movement (REM) and non‐REM (NREM) sleep and number of REM episodes in the 3 h recordings. However, a significant increase in the duration of REM episodes was observed. The AP and heart rate were increased in all phases of the cycle in rats exposed to CIH. Respiratory frequency and ventilation were similar between groups in all phases, but tidal volume was increased during NREM and REM sleep in rats exposed to CIH. An increase in the incidence of active expiration during wakefulness was observed in rats exposed to CIH. The data show that CIH‐related hypertension is not caused by changes in the sleep–wake cycle and suggest that active expiration is not required for the increase in AP in freely moving rats exposed to CIH.
Intracellular calcium stores mediate metaplasticity at hippocampal dendritic spines
Authors: Mahajan Gaurang , Nadkarni Suhita
Published: May 2019

Key points

Calcium (Ca2+) entry mediated by NMDA receptors is considered central to the induction of activity‐dependent synaptic plasticity in hippocampal area CA1; this description does not, however, take into account the potential contribution of endoplasmic reticulum (ER) Ca2+ stores.

The ER has a heterogeneous distribution in CA1 dendritic spines, and may introduce localized functional differences in Ca2+ signalling between synapses, as suggested by experiments on metabotropic receptor‐dependent long‐term depression.

A physiologically detailed computational model of Ca2+ dynamics at a CA3–CA1 excitatory synapse characterizes the contribution of spine ER via metabotropic signalling during plasticity induction protocols.

ER Ca2+ release via IP3 receptors modulates NMDA receptor‐dependent plasticity in a graded manner, to selectively promote synaptic depression with relatively diminished effect on LTP induction; this may temper further strengthening at the stronger synapses which are preferentially associated with ER‐containing spines.

Acquisition of spine ER may thus represent a local, biophysically plausible ‘metaplastic switch’ at potentiated CA1 synapses, contributing to the plasticity–stability balance in neural circuits.

Long‐term plasticity mediated by NMDA receptors supports input‐specific, Hebbian forms of learning at excitatory CA3–CA1 connections in the hippocampus. There exists an additional layer of stabilizing mechanisms that act globally as well as locally over multiple time scales to ensure that plasticity occurs in a constrained manner. Here, we investigated the role of calcium (Ca2+) stores associated with the endoplasmic reticulum (ER) in the local regulation of plasticity at individual CA1 synapses. Our study was spurred by (1) the curious observation that ER is sparsely distributed in dendritic spines, but over‐represented in larger spines that are likely to have undergone activity‐dependent strengthening, and (2) evidence suggesting that ER motility at synapses can be rapid, and accompany activity‐regulated spine remodelling. We constructed a physiologically realistic computational model of an ER‐bearing CA1 spine, and examined how IP3‐sensitive Ca2+ stores affect spine Ca2+ dynamics during activity patterns mimicking the induction of long‐term potentiation and long‐term depression (LTD). Our results suggest that the presence of ER modulates NMDA receptor‐dependent plasticity in a graded manner that selectively enhances LTD induction. We propose that ER may locally tune Ca2+‐based plasticity, providing a braking mechanism to mitigate runaway strengthening at potentiated synapses. Our study provides a biophysically accurate description of postsynaptic Ca2+ regulation, and suggests that ER in the spine may promote the re‐use of hippocampal synapses with saturated strengths.
Effect of Obstacle Type on Methane–Air Flame Propagation in a Closed Duct: An Experimental Study
Authors: Kolahdooz H. , Nazari M. , Kayhani M. H. , Ebrahimi R. , Askari O.
Published: May 2019

The combustion in a closed environment was the subject of many works in the past century due to its importance and complex nature compared with the combustion in an open environment. Most research works in this field have investigated different types of gas mixtures, the governing boundary conditions and their effect on the flame propagation structure. Additionally, several investigations have been performed on creating disturbance through obstacles in the flow path as well as the process of deflagration to detonation transition. This paper, for the first time, investigates the effect of porous and solid obstacles on the propagation and the structure of premixed methane–air flame in a closed duct with dimensions of 50 × 11 × 8 cm. The blockage created in the duct by obstacles is in such a way that the detonation process does not occur. The results for the unconstrained duct correctly represent the process of forming the classical tulip flame inside the closed duct. The location of the obstacles is changed in four different distance of 5, 10, 15, and 20 cm from the spark plug, and its effect on combustion characteristics has been evaluated. The results show that the obstacles create fundamental changes in the structure and flame propagation. A significant difference between solid and porous obstacles is that the porous obstacle, in proportion to the solid obstacle, creates less disturbance in the flow field and also does not cause excessive acceleration in the flame propagation. Porous obstacles also reduce the maximum pressure in the chamber during the process, more than the solid obstacles.
Membrane-type acoustic metamaterials with tunable frequency by a compact magnet
Authors: Zhao Junjuan , Li Xianhui , Wang Wenjiang , Wang Yueyue , Zhu Liying , Liu Yunan
Published: May 2019

In this letter, a membrane-type acoustic metamaterial with a compact magnet (MAMM) is presented. To investigate its frequency-tunable properties, a theoretical model considering both static and dynamic effects of magnetic force is established. Analytical investigations indicate that tuning of the magnetic force exerted on the centralized rigid iron platelet leads to the shift in the MAMM's transmission loss peaks. The experimental anti-resonance frequencies of the MAMM derived from the impedance tube measurements exhibited good consistency with those predicted theoretically. Continuously tuned in a wide frequency range, this structure can well adapt to the noise source variation in insulation design.
Thermal modulation of nonlinear ultrasonic wave for concrete damage evaluation
Authors: Sun Hongbin , Zhu Jinying
Published: May 2019

A nonlinear ultrasonic test is proposed for material damage evaluation using thermal modulation. Temperature change excites and modulates nonlinear behavior of ultrasonic waves in concrete. Coda wave interferometry was used to analyze the relative velocity change of ultrasonic wave with temperature variations. On concrete samples with different levels of thermal damage, experimental results indicate that the samples with a higher damage level demonstrated higher sensitivity to temperature variations. In addition, a slow dynamics nonlinear behavior was observed. When the temperature changed and then remained constant, the wave velocity gradually approached to its equilibrium value.
Luminescence of coprecipitated titanium white pigments: Implications for dating modern art
Authors: Rogge Corina E. , Arslanoglu Julie
Published: May 2019

Identification, dating and sourcing of titanium white pigments in modern art via Raman-based detection of neodymium luminescence.
Correlation between scale-invariant normal-state resistivity and superconductivity in an electron-doped cuprate
Authors: Sarkar Tarapada , Mandal P. R. , Poniatowski N. R. , Chan M. K. , Greene Richard L.
Published: May 2019

An anomalous linear-in-
H
magnetoresistance and the superconductivity are found to be correlated in an electron-doped cuprate.
Wearable thermoelectrics for personalized thermoregulation
Authors: Hong Sahngki , Gu Yue , Seo Joon Kyo , Wang Joseph , Liu Ping , Meng Y. Shirley , Xu Sheng , Chen Renkun
Published: May 2019

Wearable thermoelectrics offers personalized thermoregulation with higher energy efficiency and enhanced thermal comfort.
Lysostaphin and BMP-2 co-delivery reduces
S. aureus
infection and regenerates critical-sized segmental bone defects
Authors: Johnson Christopher T. , Sok Mary Caitlin P. , Martin Karen E. , Kalelkar Pranav P. , Caplin Jeremy D. , Botchwey Edward A. , García Andrés J.
Published: May 2019

Use of BMP-2 and lysostaphin-loaded hydrogels simultaneously clears
S. aureus
infection and repairs bone defects.
Unusual packing of soft-shelled nanocubes
Authors: Lu Fang , Vo Thi , Zhang Yugang , Frenkel Alex , Yager Kevin G. , Kumar Sanat , Gang Oleg
Published: May 2019

Nanocubes with soft DNA shells exhibit a zigzag packing with a break orientational symmetry relative to a lattice unit cell.
Angle-multiplexed all-dielectric metasurfaces for broadband molecular fingerprint retrieval
Authors: Leitis Aleksandrs , Tittl Andreas , Liu Mingkai , Lee Bang Hyun , Gu Man Bock , Kivshar Yuri S. , Altug Hatice
Published: May 2019

Angle-multiplexed dielectric metasurfaces enable sensitive molecular fingerprint detection without the need for spectrometry.
Selective trapping of hexagonally warped topological surface states in a triangular quantum corral
Authors: Chen Mu , Jiang Ye-Ping , Peng Junping , Zhang Huimin , Chang Cui-Zu , Feng Xiao , Fu Zhenguo , Zheng Fawei , Zhang Ping , Wang Lili , He Ke , Ma Xu-Cun , Xue Qi-Kun
Published: May 2019

Special constant energy contours and spin textures help to trap the Dirac fermions in topological insulators.
O10 Effect of hemodialysis dose (spKt/V) on survival in patients on maintenance hemodialysis since childhood – a retrospective analysis
Authors: Gotta V , Atkinson A , Marsenic O , Pfister M
Published: May 2019

Background

Hemodialysis (HD) prescription significantly differs between pediatric and adult patients on maintenance HD, resulting in greater difference between prescribed and delivered HD dose.1,2 HD dose targets have formally not been evaluated for children, hence targets are mainly derived from adults (spKt/V >1.4; sp: single-pool model of urea distribution, K: urea clearance, t: duration of HD session, V: urea distribution volume). This analysis aimed to evaluate the relationship between delivered dialysis dose and survival in a large cohort of patients having started HD therapy in childhood.

Methods

This retrospective analysis included a cohort of patients < 30 years (y) on chronic HD treatment since childhood, having received thrice-weekly HD between 2004 and 2016 in outpatient DaVita dialysis centers. Survival while on HD (death from any cause) was investigated using Kaplan-Meier analysis stratified by age at start of HD (0–2, >2–6, >6–12, and >12–18 y), and three mean delivered dialysis dose levels (spKt/V < 1.4, 1.4–1.6, >1.6). Survival curves between subgroups were compared using the Log-rank test.

Results

1773 patients were included in the analysis, among n=34 having started HD at age of 0–2y, n=57 at >2–6y, n=244 at >6–12y, and n=1438 at >12–18y. Median follow-up on HD ranged between 1.5 (>2–6y) to 4.7 years (>6–12y) with maximal follow-up of 23 years. Death while on HD occurred in 1/34, 6/57, 26/244, and 101/1438 patients during recorded follow-up (p=0.075, n.s.). Patients with mean spKt/V < 1.4 had lower survival on HD than those with spKt/V >1.4–1.6 (p=0.019) and those with spKt/V >1.6 (p=0.035), with 10-year survival estimated to 75% (65.2–86.2%) versus 84.5% (78.5–90.9%) and 85.0% (80.8–89.5%), respectively.

Conclusions

This is the first study to report long term survival and its relationship with delivered HD dose in patients starting HD in childhood. Our results support targeting spKt/V(urea)>1.4 in children on chronic HD treatment.

References

Gotta V, Marsenic O, Pfister M. Age- and weight-based differences in haemodialysis prescription and delivery in children, adolescents and young adults. Nephrol Dial Transplant 2018 Apr 18.

Gotta V, Marsenic O, Pfister M. Understanding urea kinetic factors that enhance personalized hemodialysis prescription in children. ASAIO J 2019 Jan 14.

Disclosure(s)

M Pfister is a consultant at Quantitative Solutions a Certara Company. V Gotta has been supported for this project by the Research Fund for Junior Researchers, University of Basel, Switzerland. O Marsenic and A Atkinson declare no financial conflict of interest.
P65 Differentiating alprostadil associated fever from infectious fever: a retrospective case-control study of neonates with ductus dependent congenital heart disease in a Tertiary Care Center
Authors: Masarwa R , Soskin S , Vardi A , Paret G , Matok I
Published: May 2019

Background

Alprostadil is used to maintain ductus patency in neonates with ductus dependent congenital heart disease (CHD), until corrective surgery. Fever is a common side effect of alprostadil and may also be a sign of infectious disease. We aimed to identify potential parameters that may differentiate infectious from alprostadil fever.

Methods

Retrospective case-control study included all neonates with ductus dependent CHD, who were admitted at the Children´s Hospital in Ramat-Gan, Israel, from August 2003 to August 2017 and developed fever on alprostadil. Cases were defined as neonates with a positive bacterial culture and controls were defined as neonates with a negative culture. Multivariate cox-regression was conducted to identify potential parameters that may differentiate alprostadil from infectious fever.

Results

Three hundred and four neonates developed fever under alprostadil. Fifty five (18%) had a positive bacterial culture and 249 (82%) had a negative culture. In univariate analysis, the duration of alprostadil infusion was 95 hours (IQR 45–116) in the case group and 72 hours (IQR 49–215) in the control group (p=0.011). The time between alprostadil initiation and fever was longer for the case group: 14.13 hours (IQR 6.5–47.5) versus 12.96 (IQR 5–30.51), (p=0.039). In multivariate cox-regression, a more than 10% increase in neutrophil count before fever was significantly associated with an increased risk for infection (HR 6.14, 95% CI 1.94–19.42). A trend towards an association was observed with CRP ≥ 10 mg/dl before fever (HR 2.5, 95% CI 0.66–9.47) and in an increase ≥ 1000 micromol/L in WBC before fever (HR 1.74, 95% CI 0.58–5.21).

Conclusions

In neonates with CHD on alprostadil therapy, an increase in neutrophil count before the appearance of fever is associated with infection. Full sepsis work-up and is still warranted in neonates who develop fever under alprostadil. Further larger studies are needed to fully establish these results.

Disclosure(s)

The authors have no conflict of interests to disclose.
P70 Identifying and managing problematic polypharmacy in children and young people?
Authors: Moss J , Austin R , Hawcutt D
Published: May 2019

Background

Polypharmacy may be necessary in a patient with complex disease or multiple illnesses. Problematic polypharmacy (PP) is defined as the prescribing of multiple medications inappropriately, or where the intended benefit of the medication is not realised. Identification and management of PP already occurs in adult medicine, with evidence based guidelines and deprescribing tools available. This work aims to establish the extent of polypharmacy affecting children at our centre, and the existence of evidence based de-prescribing guidelines to manage potential PP.

Methods

Audit of children and young people prescribed medications at a secondary and tertiary children’s hospital, January - December 2017. A systematic review looking for evidence of such a deprescribing tool or guideline was registered with PROSPERO, and undertaken. Inclusion criteria specified the need for a guideline or deprescribing tool in children from birth to < 18yrs of age. Two independent reviewers performed the review with a third reviewer resolving any discrepancies.

Results

Within a secondary and tertiary care children’s hospital, 668 children were identified as receiving >10 drugs concurrently, while 30 were receiving >20 drugs at one time.

The systematic review identified 563 papers initially, with 482 remaining once duplicates were removed. After application of inclusion and exclusion criteria, two studies were included, POPI (Prot-Labarthe et al, 2014) and PIPc (Barry et al, 2016). These papers discuss systems to identify inappropriate prescriptions. No evidence based guidelines related to the management of potential PP in children were identified.

Conclusion

There are children receiving a large number of medicines concurrently, putting them at risk of PP. No specific deprescribing guideline or tools to guide management were identified. Paediatric clinical pharmacology is well placed to create and implement such guidelines.

Disclosure(s)

Nothing to disclose
P73 Paediatric population pharmacokinetic modeling for gentamicin – is the current dose recommendation justified?
Authors: Paioni P , Berger C , Krämer SD
Published: May 2019

Background

Monitoring of gentamicin serum trough level (Cmin) is standard practice in children to prevent toxicity by accumulation1. Cmin < 2 mg/L are recommended. Peak serum concentration (Cmax) is not routinely measured although Cmax between 10 and 12 mg/L have been recommended balancing efficacy and toxicity2,3. We aimed to develop a population pharmacokinetic (PK) model for gentamicin in children to optimise current dosing regimens.

Methods

All patients receiving once daily intravenous gentamicin (5 mg/kg in children < 7 days and 7.5 mg/kg in children >7 days of age) at the University Children’s Hospital Zurich between 10/2017 and 01/2019 were eligible for this study. Children with cystic fibrosis and renal replacement procedures were excluded. Routine Cmin were measured in all patients before administration of the second or third dose. Additional gentamicin serum levels were measured 30 min (C30) and 4 h after the second dose in patients giving written informed consent. Data were analysed by non-linear mixed-effects modeling.

Results

165 patients (median age 34 days; IQR 15–56 days) were included in the study. A total number of 103 C30 and 166 Cmin measurements were available, respectively. C30 (mean 19.7 mg/L, SD ±6.1 mg/L) was >12 mg/L in 94/103 (91%) and Cmin >2 mg/mL in 3/166 (1.8%) measurements. The PK model successfully predicted most C30 >12 mg/L but performed poorly at the through levels.

Conclusions

Our current gentamicin dosing regimen rarely leads to accumulation but most Cmax are above optimal range. The latter was successfully modelled. Although no evidence for a Cmax upper limit exists, toxicity has been associated with high drug exposure3. This calls for an adjustment of our dosing regimen using our PK model based on body height or weight in order to lower exposure. Further studies investigating the relationship between Cmax levels and clinical outcome and additional data for PK model testing are needed for validation.

References

Ritz N, Bielicki J, Pfister M, van den Anker J. Therapeutic Drug Monitoring for Anti-infective Agents in Pediatrics: The Way Forward. Pediatr Infect Dis J. 2016;35(5):570–572.

Chattopadhyay B. Newborns and gentamicin-how much and how often? J Antimicrob Chemother. 2002;49(1):13–16.

Touw DJ, Westerman EM, Sprij AJ. Therapeutic drug monitoring of aminoglycosides in neonates. Clin Pharmacokinet. 2009;48(2):71–88.

Disclosure(s)

Nothing to disclose
P83 CYP2D6 phenotyping in children treated with tramadol at the Emergency Department
Authors: Rodieux F , Storelli F , Manzano S , Gervaix A , Posfay-Barbe K , Samer C , Daali Y , Desmeules J
Published: May 2019

Background

Pain management is essential and opioids side effects are of major concern. Tramadol safety and efficacy is influenced by CYP2D6 activity. Phenotyping measurement is available to assess CYP2D6 activity and allow a safe precision medicine approach.4 However need for administration of a probe drug and invasive sampling limit its use. Our objective is to evaluate direct measurement of M1/tramadol ratio and pupillometry as phenotyping methods to identify CYP2D6 ultrarapid (UM) and poor (PM) metabolizers in children treated with tramadol.1-6

Methods

We plan to include 53 children receiving their 1st dose of tramadol at the Emergency Department (ED) of the Geneva Children’s Hospital. Children with concomitant inhibitors/inducers of CYP2D6 and CYP3A or drug with an impact on pupil size are exclude. Standard CYP2D6 phenotyping is performed by measuring blood dextrorphan/dextromethorphan (DOR/DEM) using dried blood spots (DBS) at least 90min after dextromethorphan and tramadol administration. Tramadol and its active metabolite, M1, concentrations are also performed using DBS at the same time. Pupillometry is performed at time of tramadol administration and 1 to twice per hour, during the stay in the ED.

Results

We included 26 children, median age 10.7 years, of which 2 are UM (8%) and 3 PM (12%), corresponding to what is expected in the Caucasian population. We found a positive correlation between DOR/MED and M1/tramadol ratio (R2= 0.389, p = 0.0006). Pupillometry analyses are in progress. Tramadol 2 mg/kg orally was well tolerated in all children, including UM and PM.

Conclusion

Our study shows that it is possible to determine CYP2D6 activity in order to provide safe and effective tramadol prescription in children in a less invasive manner than by administering a probe drug, by directly determining the metabolic ratio between tramadol and its metabolite, M1 in children treated with tramadol

References

Fliegert, F., B. Kurth, and K. Gohler, The effects of tramadol on static and dynamic pupillometry in healthy subjects-the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status Eur J Clin Pharmacol, 2005. 61(4): p. 257–66.

Slanar, O., et al., CYP2D6 polymorphism, tramadol pharmacokinetics and pupillary response Eur J Clin Pharmacol, 2006. 62(1): p. 75–6; author reply 77–8.

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Disclosure(s)

Nothing to disclose
P85 Prediction of raltegravir plasma concentration in HIV paediatric patients using physiologically-based pharmacokinetic model
Authors: Salem F , Abduljalil K , Johnson T
Published: May 2019

Background

Raltegravir is a drug used to treat patients with HIV infection. Understanding the disposition kinetics including the ontogeny of the major metabolic enzyme (UGT1A1) is important in prediction of raltaeravir pharmacokinetics in paediatric patients.

Methods

Sim-Raltegravir compound file in Simcyp simulator version 18 was used to predict pharmacokinetics in paediatric subjects aged 4 weeks to 6 months, 0.5 to 2, 2 to 6 and 6 to 12 years. Details of trial design were matched as closely as possible with a clinical study.1 Rate of absorption and variability in first order absorption model within Simcyp were set to the reported values. Predicted plasma concentration time profiles with 5th and 95th percentile were compared with observations.

Results

The predicted vs. observed geometric mean area under plasma concentration-time profile of raltegravir was 18.4 vs. 22.3 µM.h in subjects 4 weeks to 6 months and 16.5 vs. 19.8 µM.h in those 0.5 to 2 years old. In 2 to 6 and 6 to 12 year olds around 80% and 85% of observed data were within 5th and 95th percentile of the predictions.

Conclusion

The results show that the UGT1A1 ontogeny profile in the Simcyp version 18 adequately addressed age-related differences in pharmacokinetics of raltegravir.

Reference

Rizk, M., et al, J Clin Pharmacol 2015; 55(7):748–56

Disclosure(s)

Nothing to disclose
O14 Paternal acitretin exposure and pregnancy risks
Authors: Nørgaard M , Andersen JT
Published: May 2019

Background

In the literature it is well known that acitretin is highly teratogen when used in pregnant women. Therefore, several restrictions to all fertile women prior, during and up to three years after ended treatment are recommended. However, as for paternal acitretin exposure data is very limited leading to worries and anxiety among couples planning or already pregnant.

Methods

We conducted a nationwide cohort study during the period between 1996–2016 investigating paternal acitretin exposure and the risk of spontaneous abortions and the association to major malformation. Data were obtained from the Medical Birth Registry and the National Hospital Registry. All fathers exposed to acitretin were identified by the Danish National Prescription Registry.

Results

We identified in total 1.477.252 registered pregnancies with known father identity. Of these 244 pregnancies and 205 children were exposed to paternal acitretin treatment between one year prior to conception to the end of first trimester. The adjusted hazard risk (HR) of spontaneous abortion was 0.71 (95% CI: 0.43–1.17). When analysing exposure three months prior to conception and during first trimester only, the adjusted HR was 0.76 (95% CI:0.38–1.51) and 1.06 (95% CI:0.55–2.04), respectively. As for the association between major malformation and paternal acitretin exposure between one year prior to conception to the end of first trimester the adjusted odds ratio (OR) was 1.15 (95% CI: 0.57–2.34). When stratifying for the period of acitretin exposure the same insignificant trend was detected. In addition, both spontaneous abortions and major malformation were independent of dosage.

Conclusion

We found no increased risk of spontaneous abortions or major malformation in pregnancies exposed to paternal acitretin one year before to three months after conception. This was persistent when sub-analysing exposure period and dosage. These data are an important contribute to the sparse evidence suggesting that paternal acitretin exposure during fertility is safe.

Disclosure(s)

Nothing to disclose
P118 ‘Medicines for Children’ project: putting families and carers in the centre
Authors: Zolotas E , Sammons H , Tuthill D , Barker C , Tomlin S , Partridge L , Rossiter A , Osmond V , Barham H , Fox A ,   Medicines For Children Project Board
Published: May 2019

Background

‘Medicines for Children’ (MfC) is a joint initiative between the children´s charity WellChild, the Royal College of Paediatrics and Child Health and the Neonatal and Paediatric Pharmacists Group. The project aim is to provide parents and carers with reliable, accurate and accessible information about their child’s medicines.

Methods

In 2006, 600 parents and carers were surveyed in order to understand what information was needed. Paediatricians, pharmacists and a medical editor then liaised with WellChild to develop a leaflet template and wrote a set of pilot leaflets. The leaflet production was subsequently standardised. An eight-step process is followed including consultation with health professionals, families and carers. The leaflet library and a series of information videos has grown, with the assistance of a dedicated group of volunteer authors. Published leaflets are reviewed every three years. Access to information is free of charge. The project is funded by the 3 partner groups and not by pharmaceutical companies.

Results

MfC hosts over 230 leaflets and videos. The MfC website1 was launched in 2009. It was subsequently reviewed by parents and carers and re-developed in 2011 and 2015. MfC has users accessing the site from every country in the world. The information leaflets have been viewed over 3 million times in 2018, up from 7,200 in 2009. In 2014, an independent audit of MfC found that over 90% of the parents surveyed thought that the leaflets had an appropriate layout and conveyed the information in lay terminology. Since 2011, MfC information leaflets have been certified by National Health Service Information Standard as providing high quality health information for the public.

Conclusion

MfC is a successful and acclaimed project which provides high quality, reliable and accurate medicines information worldwide for more than a decade.

Reference

https://www.medicinesforchildren.org.uk/.

Disclosure(s)

Nothing to disclose.
O02 Developmental pharmacogenetics of SLCO2B1 on montelukast pharmacokinetics in chinese children
Authors: Li Q , Wang K , Shi H-Y , Y-E Wu , Zhou Y , Kan M , Zheng Y , Hao G-X , Yang X-M , Yang Y-L , L-Q Su , Wang X-L , Jacqz-Aigrain E , Zhao W
Published: May 2019

Background

Montelukast, a potent orally selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma.Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed significant inter-individual variability on pharmacokinetics.None of pharmacokinetic study has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of this study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1on Montelukast pharmacokinetics in Chinese paediatric patients.

Methods

After oral administration with montelukast, opportunistic samples were collected from asthma children and plasma concentrations were determined by high performance liquid chromatography coupled with fluorescence detector (HPLC-FLD) method. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped.

Results

Fifty patients (age range 0.7–10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in subjects with SLCO2B1 c.935GA and c.935AAgenotype compared withSLCO2B1 c.935GGsubjects (0.94±0.26 versus 0.77±0.21, p=0.020). Weight was also found to be significantly corrected with montelukast clearance (p 0.0001).

Conclusions

The developmental pharmacogenetics of montelukast in Chinese children was evaluated. Weight and SLCO2B1 genotype showed independently significant impacts on theclearanceofmontelukast.

Disclosure(s)

Nothing to disclose.
O21 Progress towards Therapeutic Drug Monitoring via breath analysis
Authors: Singh KD , Ziesenitz V , Usemann J , Van Den Anker J , Frey U , von der Weid N , Datta A , Sinues P
Published: May 2019

Background

Therapeutic Drug Monitoring (TDM) is essential aspect for the clinical management of patients. However, despite the clear advantages of TDM, it faces several challenges to being more widely used in the clinic. Specially challenging is the case of TDM in children, as they experience rapid physiologic developments, leading to great pharmacokinetic and pharmacodynamic variability. Breath analysis provides a patient-friendly approach to support TDM. To explore this possibility, we are currently running a pilot study, whereby we analyze the exhaled breath of pediatric patients receiving anti-seizure or chemotherapy drugs requiring TDM.

Methods

We analyzed by secondary electrospray ionization-high resolution mass spectrometry (SESI-HRMS) exhaled breath of pediatric patients under therapy for Valproic acid (VPA; n = 27), Lamotrigine (n = 19), Levetiracetam (n = 15), Oxcarbazepine (n = 11) and Methotrexate (n = 4). Systemic blood concentrations were measured simultaneously to the breath test. In the case of VPA, we constructed a regression model to predict systemic blood concentrations based on the signal intensity of breath mass spectral features. For the rest of the drugs listed, due to its current limited size, we conducted preliminary data visualization approaches.

Results

We found that exhaled metabolites of VPA allow to predict free VPA blood concentrations with a root-mean-square error of 1.5 mg/L for concentrations in the range 0–12 mg/L. This prediction is accomplished within 20 minutes, comprising the breath test and data analysis. For Levetiracetam, Lamotrigine and Oxcarbazepine the data analysis is still ongoing. For MTX we found breath metabolites clearly altered as a result of the drug administration. However, a great inter-individual variability was also observed.

Conclusion

We conclude that breath analysis may support current TDM approaches. This will lead to new opportunities to guide the dose of drugs with a high level of accuracy, in real-time and non-invasively.

Disclosure(s)

PS gratefully acknowledges the financial support of the Fondation Botnar (Switzerland) and the Swiss National Science Foundation (320030_173168 and PCEGP3_181300). PS is part of the board of directors of Deep Breath Initiative AG. JU was supported by research fellowship of the University Children’s Hospital Basel. VS and JVDA were supported by the Eckenstein-Geigy Foundation. *AD and PS: shared senior authorship