bluuebunny/crossref_metadata_2025 huggingface dataset:
Shared decision making: A dual‐layer model to tackling multimorbidity in primary care
Authors: Ng Chirk Jenn , Lee Yew Kong , Abdullah Adina , Abu Bakar Ahmad Ihsan , Tun Firzara Abdul Malik , Tiew Han Wei
Published: May 2019

It is common for primary care providers (PCPs) to manage complex multimorbidity. When caring for patients with multimorbidity, PCPs face challenges to tackle several issues within a short consultation in order to address patients' complex needs. Furthermore, some PCPs may lack access to a multidisciplinary team and need to manage multimorbidity within the confine of a PCP‐patient partnership only. Instead of attempting to address multiple health issues within a single consultation, it would be more feasible and time effective for PCPs and patients to jointly prioritize the health issue to focus on. Using the Malaysian primary care setting as a case study, a dual‐layer‐shared decision‐making approach is proposed whereby PCPs and patients make decisions on which disease(s) (layer 1) and treatment(s) (layer 2) to prioritize. This dual‐layer model aims to address the challenges of short consultation time and limited healthcare resources by encouraging PCPs and patients to discuss, negotiate, and agree on the decision during the consultation to ensure patients' health needs are addressed.
Employment in the Great Recession: How Important Were Household Credit Supply Shocks?
Authors: GARCÍA DANIEL
Published: May 2019

I pool data from all large multimarket lenders in the United States to estimate how many of the over 7 million jobs lost in the Great Recession can be explained by reductions in the supply of mortgage credit. I construct a mortgage credit supply instrument at the county level, the weighted average (by prerecession mortgage market shares) of liquidity‐driven lender shocks during the recession. The reduction in mortgage supply explains about 15% of the employment decline. The job losses are concentrated in construction and finance.
Family‐centred care of children and young people in the acute hospital setting: A concept analysis
Authors: O'Connor Siobhán , Brenner Maria , Coyne Imelda
Published: May 2019

Aims and objectives

To provide an operational definition of family‐centred care as it applies to hospitalised children. The objective was to provide clarification of the concept by comprehensively analysing the evidence.

Background

Terms associated with family‐centred care include partnership‐in‐care, negotiated care, parental participation/involvement in care, care‐by‐parent and child‐centred care. The absence of a universally accepted definition contributes to its inconsistent implementation.

Design and Methods

Concept analysis is acknowledged as a form of inquiry to develop the knowledge base of nursing. Rodgers' evolutionary approach to concept analysis was used as a guiding framework. The systematic literature search yielded 30 theoretical papers; the results are outlined on a PRISMA flow diagram.

Results

Surrogate terms identified include partnership‐in‐care, negotiated care and parent participation. Parental participation in care, the development of respectful and trusting partnerships, information sharing and all family members as care recipients were identified as attributes to family‐centred care. There is limited evidence that family‐centred care enhances the child's, parents' and families' experience of hospitalisation and is associated with reduced anxiety for parents.

Conclusion

There is a lack of attention to cultural and societal changes, which impact on those receiving and delivering care. While we know that family‐centred care is widely endorsed and enhances well‐being, there is a lack of empirical evidence about the impact on health outcomes for children. While children's nurses have been applying some elements of family‐centred care to their clinical practice for decades, the concept continues to evolve.

Relevance to clinical practice

Further research examining the effects of family‐centred care for children, their families, healthcare professionals and healthcare organisations reflecting cultural diversity and norms must be conducted. This research should include the effects of family‐centred care on parents caring for their child in hospital, how family‐centred care supports parents to make healthcare decisions and the outcomes of family‐centred care for children and families.
Obstetrical outcomes after first‐trimester chorionic villus sampling in twin pregnancies: A retrospective case–control study
Authors: Kim Mi S. , Ahn Eunhee , Lee Soo B. , Moon Myoung J. , Kang Sukho
Published: May 2019

Aim

Prenatal diagnostic testing by chorionic villus sampling (CVS) is sometimes recommended for women with twin pregnancies. However, few studies have compared the outcomes between twins with CVS and control twins without intervention. This study aimed to compare the obstetrical outcomes of CVS in twin pregnancies and those in non‐intervention twin pregnancies.

Methods

First‐trimester transabdominal CVS was performed on dichorionic‐diamniotic twins (n = 54; Group 1) between December 2006 and January 2017 at the Department of Obstetrics and Gynecology at our hospital, and the data were retrospectively analyzed. CVS risks were evaluated by comparing obstetrical outcomes with those of a control population of 155 dichorionic‐diamniotic twins without intervention (Group 2).

Results

The difference in the overall fetal loss rate (Group 1, 7.4% vs Group 2, 3.9%; P = 0.287) between the two groups was not statistically significant. The miscarriage rate, defined as delivery at <24 gestational weeks, and early preterm delivery, defined as delivery at <34 gestational weeks, were not significant between the groups (miscarriage: Group 1, 5.6% vs Group 2, 3.2%; P = 0.428; early preterm delivery: Group 1, 11.1% vs Group 2, 9.0%; P = 0.788). The mean gestational age at delivery, birth weights and neonatal intensive care unit admission rate were not statistically significant between the groups. Thus, the overall fetal loss rate and obstetrical outcomes of Group 1 were comparable with those of Group 2.

Conclusion

In conclusion, the overall obstetrical outcomes were not significantly different between twins with CVS and control twins with the advantage of enabling early decision‐making about selective feticide in twins with CVS.
Arms races with mitochondrial genome soft sweeps in a gynodioecious plant, Plantago lanceolata
Authors: Bergero Roberta , Levsen Nick , Wolff Kirsten , Charlesworth Deborah
Published: May 2019

Biological situations involving conflict can create arms race situations with repeated fixations of different functional variants, producing selective sweeps and lowering neutral diversity in genome regions linked to the functional locus. However, they can sometimes lead to balancing selection, potentially creating long coalescent times for sites with functionally different variants, and, if recombination occurs rarely, for extended haplotypes carrying such variants. We tested between these possibilities in a gynodioecious plant, Plantago lanceolata, in which cytoplasmic male‐sterility factors conflict with nuclear restorers of male fertility. We find low mitochondrial diversity, which does not support very long‐term coexistence of highly diverged mitochondrial haplotypes. Interestingly, however, we found a derived haplotype that is associated with male fertility in a restricted geographic region, and that has fixed differences from the ancestral sequence in several genes, suggesting that it did not arise very recently. Taken together, the results suggest arms race events that involved “soft" selective sweeps involving a moderately old‐established haplotype, consistent with the frequency fluctuations predicted by theoretical models of gynodioecy.
Making every calorie count
Authors: Buttriss J. L.
Published: May 2019

We live in a world where people are living longer and overweight and obesity are widespread, linked with a calorie intake in excess of the requirements of a sedentary lifestyle. Obesity is known to increase the chance of developing type 2 diabetes and other chronic diseases. But is achieving energy balance the only challenge we face or is the scenario more complex? Evidence from dietary surveys indicates that calories should not be considered in isolation because poor diets are widespread, even in countries such as the UK. The National Diet and Nutrition Survey provides evidence of relatively low intakes of a number of essential vitamins and minerals among UK teenagers and young adults, in particular, and low intakes of fibre in all age groups, associated with low intakes of wholegrain foods, vegetables, fruit and pulses. Despite widespread familiarity with the 5 A DAY message, only 27% of adults eat five portions of fruit and vegetables a day and, on average, teenagers have particularly low intakes. The poor quality of many diets in Britain has been brought into sharp focus by publication of time trend data showing that micronutrient intakes have worsened over the past decade. However, going forward, dietary recommendations need to be considered in the context of delivering a global food supply that is both nutritious and also environmentally sustainable, and takes into account other factors such as equitable access, affordability and acceptability.
Deep learning for identification of fasciculation from muscle ultrasound images
Authors: Nodera Hiroyuki , Takamatsu Naoko , Yamazaki Hiroki , Satomi Ryutaro , Osaki Yusuke , Mori Atsuko , Izumi Yuishin , Kaji Ryuji
Published: May 2019

Background

Detection of fasciculation plays a significant role in the early diagnosis of amyotrophic lateral sclerosis (ALS). Although ultrasound (US) has been reported to be superior to needle electromyography (EMG) and visual inspection in terms of detection rates, other similar movements could lower the reliability of the result. Artificial intelligence, such as deep learning, promises to enhance the classification of visual data.

Aim

To classify fasciculation and its mimics by deep learning.

Methods

Using an 11‐MHz linear‐array transducer, muscle US was recorded from the biceps brachii and tibialis anterior muscles. Fasciculation for patients with ALS, and movements of voluntary muscles or the recording probe of healthy individuals were recorded. Background subtraction was performed to obtain binary images to infer movements. Deep learning was performed using five different networks with and without pre‐trained weights.

Results

Three groups of images were divided into training, validation, and test (fasciculation: N = 1473; voluntary movement: N = 861; probe movement: N = 1626). The accuracy of detection with pre‐trained weights (fine‐tuning) ranged from 0.959 to 1.0. The best accuracy was obtained by VGG16/19 convolutional neural networks and the ResNet‐152 network. Accuracy of prediction was considerably lower without the pre‐trained weights. The mean white pixels (inferring movements) were lower in fasciculation than in the voluntary and probe movement groups; however, the non‐fasciculation groups showed similar pixel counts (P = 0.95).

Conclusions

US accurately distinguished between fasciculation and its mimics by deep learning. Pixel counting could be a reliable quantitative method to detect fasciculation.
Reduction of mitochondria and up regulation of pyruvate dehydrogenase kinase 4 of skeletal muscle in patients with chronic kidney disease
Authors: Xu Chenqi , Kasimumali Ayijiaken , Guo Xiangjiang , Lu Renhua , Xie Kewei , Zhu Mingli , Qian Yingying , Chen Xiaohuan , Pang Huihua , Wang Qin , Fan Zhuping , Dai Huili , Mou Shan , Ni Zhaohui , Gu Leyi
Published: May 2019

Aim

Muscle weakness is commonly among chronic kidney disease (CKD) patients. Muscle mitochondrial dysfunction and decreased pyruvate dehydrogenase (PDH) activity occur in CKD animals but have not been confirmed in humans, and changes in pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) expression have not been evaluated in CKD muscle. We presume that the reduction of muscle mitochondria and post‐translational modification of PDH may cause muscle weakness in CKD patients. Herein, we explored changes in mitochondrial morphology, PDH expression and activity, and PDK/PDP expression in CKD patient muscle.

Methods

Twenty patients with stage 4–5 CKD (CKD group) and 24 volunteers (control group) were included. Clinical characteristics, biochemical information and handgrip strength (HGS) were determined. Skeletal muscle samples were collected from eight stage 5 CKD patients from CKD group. Other eight non‐CKD surgical subjects’ muscle samples were collected as control. PDH activity was determined using a PDH enzyme activity assay kit, and real‐time PCR and western blotting analyses were performed to measure gene expression and protein levels, respectively. Transmission electron microscopy was used to study mitochondria morphology.

Results

CKD patients had lower HGS than non‐CKD subjects, and HGS was correlated with gender, age, haemoglobin and albumin. Mitochondria were decreased in end‐stage renal disease (ESRD) patients muscle. Mfn‐1 expression and phospho‐Drp1(S637)/Drp1 ratio were inhibited in the ESRD group, implicating dysfunctional mitochondrial dynamics. Muscle PDH activity and phospho‐PDH(S293) were decreased in ESRD patient muscle, while PDK4 protein level was up regulated.

Conclusion

Decreased mitochondria and PDH deficiency caused by up regulation of PDK 4 contribute to muscle dysfunction, and could be responsible for muscle weakness in CKD patients.
The sucrose‐to‐malate ratio correlates with the faster CO2 and light stomatal responses of angiosperms compared to ferns
Authors: Lima Valéria F. , Anjos Letícia dos , Medeiros David B. , Cândido‐Sobrinho Silvio A. , Souza Leonardo P. , Gago Jorge , Fernie Alisdair R. , Daloso Danilo M.
Published: May 2019

Stomatal responses to environmental signals differ substantially between ferns and angiosperms. However, the mechanisms that lead to such different responses remain unclear.

Here we investigated the extent to which leaf metabolism contributes to coordinate the differential stomatal behaviour among ferns and angiosperms.

Stomata from all species were responsive to light and CO2 transitions. However, fern stomatal responses were slower and minor in both absolute and relative terms. Angiosperms have higher stomatal density, but this is not correlated with speed of stomatal closure. The metabolic responses throughout the diel course and under different CO2 conditions differ substantially among ferns and angiosperms. Higher sucrose content and an increased sucrose‐to‐malate ratio during high CO2‐induced stomatal closure was observed in angiosperms compared to ferns. Furthermore, the speed of stomatal closure was positively and negatively correlated with sugars and organic acids, respectively, suggesting that the balance between sugars and organic acids aids in explaining the faster stomatal responses of angiosperms.

Our results suggest that mesophyll‐derived metabolic signals, especially those associated with sucrose and malate, may also be important to modulate the differential stomatal behaviour between ferns and angiosperms, providing important new information that helps in understanding the metabolism‐mediated mechanisms regulating stomatal movements across land plant evolution.
Evaluating a smartwatch notification system in a simulated nursing home
Authors: Ali Haneen , Li Huiyang
Published: May 2019

Aims

This paper evaluates a high‐fidelity prototype of a smartwatch‐based communication system for nursing homes. The system could improve communication between residents and caregivers, thus reducing staff response time and improving residents' safety.

Background

Across the country, nursing homes are often cited as having serious quality and safety issues. Deficiencies in the communication systems that connect residents with caregivers significantly impact the quality of care. Most nursing homes still use traditional call light systems, that give visual and auditory cues to caregivers, who may or may not be in proximity to the system. This study evaluates a smartwatch communication system developed to quickly relay a resident's requests for assistance to staff anywhere in the nursing home.

Method

Certified Nursing Assistants (CNAs) employed by nursing homes were recruited to perform routine tasks using both a traditional system and a smart system. Response time to call lights, staff performance and outcomes were measured through direct and recorded observations and through the surveys of participants.

Results

The smartwatch system reduced staff response time to call lights from bedrooms by 40%, from bathrooms by 58% and from bed exit alarms by 29%. The smartwatch system also reduced perceived workload by about 50% and was highly accepted by the CNAs.

Conclusion

A smartwatch‐based notification system may increase staff performance and decrease workload, thus leading to greater staff and patient satisfaction, which could ultimately lead to better quality of care and patient safety.

Relevance to clinical practice

This study provides empirical evidence for the usefulness of smartwatches in facilitating the notification and communication processes in healthcare settings and is also among the first to actually examine a smartwatch system in a healthcare setting.
A qualitative assessment of a dog program for youth offenders in an adult prison
Authors: Smith Hayden P. , Smith Holly
Published: May 2019

Objective

Dog programs occurring in prison tend to generate positive public opinion and media portrayals, yet they often lack empirical validation. This is the first study to examine the key themes that drive a dog program aimed at incarcerated youth serving time in an adult prison.

Design and Sample

A sample of male youth (n = 31) were provided survey questions on a rescue dog program. A grounded qualitative approach was employed with open‐ended responses.

Results

The following themes emerged: the symbolism of the dog its role in therapy, perceptions of positive behaviors and rehabilitation, a sense of normality, and universal support by inmates.

Conclusion

This study supports the potential for utilizing rescue dogs in therapeutic interventions in which the vulnerable inmate can discuss early trauma, interpersonal dysfunction and histories of deviance. The dog symbolized the potential for incarcerated youth to engage in discussion of sensitive topics in a safe manner. Policy implications also include the function of dogs in creating a normalizing effect on the prison unit itself, one that can promote rehabilitation. There was universal support for the program which is rare in the prison milieu. Theoretically, positive outcomes occurred in an indirect manner, though more research is needed.
Gene drives and the international biodiversity regime
Authors: Rabitz Florian
Published: May 2019

Gene drives are genetic modifications designed for rapidly diffusing traits throughout a target population. They are currently being proposed as biological control agents to combat, for instance, invasive alien species and disease vectors. They also raise concerns regarding their potential adverse effects on biological diversity. This text assesses gene drive governance under the Convention on Biological Diversity (CBD) and its Cartagena Protocol on Biosafety. While gene drives are directly relevant for the objectives of both agreements, their regulatory frameworks have not kept up with the pace of technological change. The focus of this article is on the analysis of gaps and inconsistencies within both agreements. It highlights numerous elements of the CBD and the Cartagena Protocol that raise challenges for gene drive governance, such as matters related to regulatory scope, transboundary movements, precaution and invasive alien species.
Single‐breath comprehensive cardiopulmonary assessment utilizing computerized tomography
Authors: Leong Paul , MacDonald Martin I. , Ko Brian S. , Lau Kenneth K. , Troupis John M. , Bardin Philip G.
Published: May 2019

Watch the video abstract

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Age‐related physical and technical match performance changes in elite soccer players
Authors: Sal de Rellán‐Guerra Alejandro , Rey Ezequiel , Kalén Anton , Lago‐Peñas Carlos
Published: May 2019

The age of peak performance is likely to vary between sports and competitions, affected by the specific skills and attributes needed to succeed in the particular competition. However, no studies using modern tracking techniques have examined the effects of age on competitive match play performance. Thus, the purpose of this study was to evaluate the effects of age on match physical and technical performance using a large‐scale analysis of match performance in professional soccer players. A total of 14 546 individual match observations were undertaken in the first German league (Bundesliga) during the 2012‐2013, 2013‐2014, and 2014‐2015 seasons using a computerized tracking system (VISTRACK, by Impire Corp.). Differences in physical and technical match performance of soccer players were analyzed for the following variables: total distance covered, number of fast runs, number of sprints, and percentage of successful passes. Professional soccer players aged >30 years showed a significant lower performance in the total distance covered, the number of fast runs, and the number of sprints compared with younger players (≤30 years). Conversely, the player's ability to make successful passes increased with age. These effects were observed in all positional roles except wide midfielders. These findings may help coaches and managers to better understand the effects of age on match‐related physical and technical performance and may have the potential to assist in decisions such as, when a new contract would be signed, the duration of the contract, the salary, or when to replace or transfer a player depending on their age.
Transferability of faculty development resources
Authors: Olupeliyawa Asela M. , Venkateswaran Sunil , Wai Nyunt , Mendis Kumara , Flynn Eleanor , Hu Wendy
Published: May 2019

Background

Adapting existing training resources for clinical teachers is more efficient than creating resources de novo. There is limited evidence on how to effectively use and ensure the relevance of training materials originally developed for different contexts and audiences. We tested in Sri Lanka and Malaysia the transferability of scenario‐based training videos and session plans developed for Australian medical schools, to identify those aspects which need adaptation, and make recommendations to enhance transferability.

Methods

Staff involved in student support from three medical schools were invited to participate in five workshops facilitated by an Australian educator. Video discussion triggers of students presenting with concerns were used in workshop activities, including written exercises, group discussions and reflection. The quantitative and qualitative data collected included categorical and free‐text participant responses to questionnaires and structured field notes from local faculty developers using peer observation.

Findings

Academic and clinician‐teacher participants predominated in the workshops. Of 66 participant questionnaires (92% response rate), over 90% agreed that the workshop was relevant, and over 95% agreed that the videos facilitated discussion and the sharing of experiences. Field notes confirmed that participants were engaged by the videos, but identified that one student scenario and the approaches for seeking support in others were not immediately transferable to local contexts. The adaptation of facilitation techniques used in Australian workshops was needed to address audience responses.

Discussion

Our findings confirm faculty development principles of content relevancy and incorporation of reflection. To enhance transferability, we recommend co‐facilitation with local faculty members, the explicit signposting of topics and re‐contextualising key concepts through reflective discussion.
Combustion Ionization for Detection of Misfire, Knock, and Sporadic Preignition in a Gasoline Direct Injection Engine
Authors: Ayad Samuel , Sharma Swapnil , Verma Rohan , Henein Naeim
Published: May 2019

Detection of combustion-related phenomena such as misfire, knock, and sporadic preignition is very important for the development of electronic controls needed for the gasoline direct injection engines to meet the production goals in power, fuel economy, and low emissions. This paper applies several types of combustion ionization sensors, and a pressure transducer that directly senses the in-cylinder combustion, and the knock sensor which is an accelerometer that detects the impact of combustion on engine structure vibration. Experimental investigations were conducted on a turbocharged four-cylinder gasoline direct injection engine under operating conditions that produce the above phenomena. One of the cylinders is instrumented with a piezo quartz pressure transducer, MSFI (multi-sensing fuel injector), a stand-alone ion current probe, and a spark plug applied to act as an ion current sensor. A comparison is made between the capabilities of the pressure transducer, ion current sensors, and the knock sensor in detecting the above phenomena. The signals from in-cylinder combustion sensors give more accurate information about combustion than the knock sensor. As far as the feasibility and cost of their application in production vehicles, the spark plug sensor and MSFI appear to be the most favorable, followed by the stand-alone mounted sensor which is an addition to the engine.
Applying Semantic Web Technologies to Provide Feasibility Feedback in Early Design Phases
Authors: Ocker Felix , Vogel-Heuser Birgit , Paredis Christiaan J. J.
Published: May 2019

In the product development process, as it is currently practiced, production is still often neglected in the early design phases, leading to late and costly changes. Using the knowledge of product designers concerning production process design, this paper introduces an ontological framework that enables early feasibility analyses. In this way, the number of iterations between product and process design can almost certainly be reduced, which would accelerate the product development process. Additionally, the approach provides process engineers with possible production sequences that can be used for process planning. To provide feasibility feedback, the approach presented relies on semantic web technologies. An ontology was developed that supports designers to model the relations among products, processes, and resources in a way that allows the use of generic Sparql Protocol And RDF Query Language (SPARQL) queries. Future applicability of this approach is ensured by aligning it with the top-level ontology Descriptive Ontology for Linguistic and Cognitive Engineering (DOLCE). We also compare the ontology’s universals to fundamental classes of existing knowledge bases from the manufacturing and the batch processing domains. This comparison demonstrates the approach’s domain-independent applicability. Two proofs of concept are described, one in the manufacturing domain and one in the batch processing domain.
Acoustically driven oscillatory flow fields in a cylindrical resonator at resonance
Authors: Farouk Bakhtier , Antao Dion S. , Hasan Nusair
Published: May 2019

Generation and development of acoustic waves in an air-filled cylindrical resonator driven by a conical electro-mechanical speaker are studied experimentally and simulated numerically. The driving frequencies of the speaker are chosen such that a standing wave field is produced at each chosen frequency in the resonator. The amplitude of the generated acoustic (pressure) waves is measured along the axis of the resonator by a fast response piezo-resistive pressure transducer, while the radial distribution of the oscillatory axial velocities is measured at the corresponding velocity anti-node locations by a constant temperature hot-film anemometer. For the cases studied, the acoustic Reynolds number ranged between 20.0 and 60.0 and the flow fields were always found to be in the laminar regime. The flow field in the resonator is also simulated by a high-fidelity numerical scheme with low numerical diffusion. Formation of the standing wave and quasi-steady acoustic streaming are numerically simulated by solving the fully compressible form of the Navier-Stokes equations. The effects of the sound field intensity (i.e., input power to the speaker) and driving frequency on the standing wave field and the resultant formation process of the streaming structures are also investigated.
B cells engineered to express pathogen-specific antibodies protect against infection
Authors: Moffett Howell F. , Harms Carson K. , Fitzpatrick Kristin S. , Tooley Marti R. , Boonyaratanakornkit Jim , Taylor Justin J.
Published: May 2019

B cells reprogrammed to express pathogen-specific antibodies using CRISPR-Cas9 protect against infection.
P66 Characterization of the pharmacokinetics of acetaminophen and its metabolites in the fetus through integration of placental transfer in a physiologically based pharmacokinetic model
Authors: Mian P , Allegaert K , Conings S , Annaert P , Tibboel D , Pfister M , van Calsteren K , van den Anker JN , Dallmann A
Published: May 2019

Background

Little is known about fetal acetaminophen (paracetamol) pharmacokinetics and its potential for toxicity, despite the frequent use of acetaminophen during pregnancy. The aim of this study was to develop a feto-maternal physiologically based pharmacokinetic model (f-m PBPK) to predict placental transfer and PK of acetaminophen and its metabolites in fetus at term pregnancy.

Methods

Previously, a pregnancy PBPK model was developed for prediction of maternal PK of acetaminophen and its metabolites. This model was structurally extended with the fetal liver, and quantitative information on the maturation of relevant enzymes was integrated. Three different approaches (ex vivo placenta perfusion experiments, scaling of passive diffusion transfer rates, and the Mobi® default method) to describe placental drug transfer were tested. Predicted maternal and fetal acetaminophen concentrations were compared with those observed in the literature. umbilical cord data at birth.

Results

The 3 different approaches to predicted acetaminophen PK in the umiblical vein were found to yield broadly similar results. Acetaminophen exposure was similar in maternal blood compared to venous umbilical cord blood. Prediction of the median dose fraction of acetaminophen converted to its metabolites (fm) revealed higher maternal acetaminophen-glucuronide formation clearance and sulphate formation compared to that in the fetal liver (fm_glucuronide52.2 vs 0% and fm_sulphate30.4 vs 0.8%, respectively) and higher fraction of acetaminophen converted to the reactive metabolite N-acetyl-p-benzoquinone-imine (fm_NAPQI, 6.5 vs 0.06%) in pregnant women compared to their fetus.

Conclusion

No differences were observed in the 3 approaches for integration of placental drug transfer. Differences in acetaminophen biotransformation to its metabolites between pregnant women and their fetuses were quantitatively predicted.

Disclosure(s)

Paola Mian received a Short term Minor (STM-2017) grant from the Stichting Sophia Kinderziekenhuis fonds to conduct this research.
P67 Impact of enantiomer-specific maturational changes in pharmacokinetics on the racemic ketorolac target trough concentration
Authors: Cloesmeijer M , Krekels E , van Esdonk M , Lynn A , Smits A , Tibboel D , Daali Y , Olkkola K , Allegaert K , Mian P
Published: May 2019

Introduction

Ketorolac is a racemic drug with analgesic effects specific to its S-enantiomer. This study aimed to describe enantiomer-specific maturational pharmacokinetics (PK). Simulations were performed to describe how S-ketorolac exposure in infants differs from adults, and how this affects the adult racemic analgesic trough threshold EC50 (EC50thr-adult, 0.37 mg/L) in infants (EC50thr-infant)when the same S-target is applied.

Methods

A population PK analysis (NONMEM 7.3) was performed based on 1020 plasma samples from 5 studies including 80 patients (adults, children, infants) following single intravenous ketorolac administration.

Results

S-ketorolac PK was best described with a 2-compartment model in infants and 3-compartment model in adults, while R-ketorolac PK was best described with a 2-compartment model in all. S-ketorolac clearance [mean population value: 3.45 L/h/56 kg] and central volume of distribution (V1) [4.27 L/56kg] increased exponentially with bodyweight (0.75, 0.59 respectively). R-ketorolac clearance [0.93 L/h/56kg], peripheral volume of distribution (V2) and inter-compartmental clearance (Q) increased exponentially with bodyweight (0.62, 1.20, 0.76 respectively), V1 [4.11 L/56kg] linearly with bodyweight. Simulations revealed EC50thr-adult (0.37 mg/L) contained 0.048 mg/L S-ketorolac as mean in typical adults (BW 48.6–99.6 kg), while EC50thr-adult contained 0.032–0.036 mg/L S-ketorolac in typical infants (BW 5.3–10.6 kg). To reach adult S-enantiomer concentration (0.048 mg/L) in typical infants (BW 5.3–10.6 kg), EC50thr-infant should be 0.49–0.46 mg/L, respectively.

Conclusion

Enantiomer-specific maturational PK of ketorolac were described. Subsequent simulations displayed differences in proportion of S- and R-ketorolac on the racemic threshold EC50. A The same S-ketorolac concentration necessitates a higher EC50thr-infant to EC50thr-adult.

Disclosure(s)

Nothing to disclose
P71 Population pharmacokinetics and pharmacogenetics of caffeine in Chinese premature infants with apnoea of prematurity
Authors: Ni S , Gao X-B , Y-E Hu , Wang C-H , Jiang Z-H , Yang F , Zheng Y , Zhao W
Published: May 2019

Background

Caffeine is commonly regarded as the treatment of choice for neonatal apnoea. However, limited data on the developmental pharmacokinetics and pharmacogenetics were available in Chinese premature infants. The objective of this study was to develop a population pharmacokinetic model of caffeine after intravenous administration to Chinese neonates with apnoea of prematurity (AOP) and evaluate the impact of developmental pharmacogenetics of CYP1A2.

Methods

Sparse pharmacokinetic samples were collected from AOP newborns receiving caffeine citrate at a loading dose of 20 mg/kg/d and maintenance dose of 5–10 mg/kg/d. Population pharmacokinetic-pharmacogenetic analysis of caffeine was performed using NONMEM. Eight CYP1A2 polymorphisms were genotyped.

Results

A total of 99 newborns with a mean (SD) postmenstrual age of 32.0 (2.16) (range 22.3 - 38.0) weeks were included in the present study. Pharmacokinetic data fitted an one-compartment model with first-order absorption and elimination. Current weight, postmenstrual age and serum creatinine concentration were significant covariates influencing caffeine clearance. None of tested CYP1A2 polymorphisms had significant impact on caffeine pharmacokinetics.

Conclusion

The population pharmacokinetics-pharmacogenetics of caffeine was evaluated in Chinese AOP premature infants. This developmental pharmacokinetic model can be helpful to individualize caffeine therapy.

Disclosure(s)

Nothing to disclose
P72 Maturation of sildenafil clearance in prematurely born infants with BPD associated pulmonary hypertension
Authors: Nikrawesh H , Engbers AGJ , Völler S , Simons SHP , Koch BCP , Knibbe CAJ , Reiss IKM , Flint RB
Published: May 2019

Background

Sildenafil is used as an off-label treatment for bronchopulmonary dysplasia (BPD) associated pulmonary hypertension in prematurely born infants. As there is only limited information on the pharmacokinetics (PK) of sildenafil in this population, the aim of this study is to investigate the PK of sildenafil in prematurely born infants with BPD associated pulmonary hypertension.

Method

In this multicentre study, a population PK model for sildenafil in prematurely born infants was developed based on samples obtained using opportunistic sampling during clinical use of sildenafil. Data of seven subjects (42 plasma samples) were analysed by nonlinear mixed-effect modelling (NONMEM®7.3). Median (range) gestational age (GA) was 26.1 (24.1–27.6) weeks, current bodyweight 1960 (632–3157) grams, birthweight 635 (465–1125) grams and postnatal age (PNA) at start of therapy 64.9 (10.9–89) days. The median (range) treatment duration was 4.9 (1.6–13.1) weeks, with six subjects receiving oral doses of median 2.6 mg/kg/day (1.5–5.3) in three doses and one subject receiving oral and intravenous doses of 6.7 mg/kg/day in two doses.

Results

The plasma concentration time profiles of sildenafil were best described by a one compartment model. Clearance (CL) and volume of distribution (Vd) for a child with a PNA of 64.9 days and bodyweight of 1.96 kg was 4.42 L/h ((RSE) 11%) and 29.5 L (32%), respectively. PNA was found to significantly influence CL, resulting in an increase of 10.7% in a week, and 43% in a month for a 65-day old infant. No other covariates (i.e. bodyweight, birthweight, GA, postmenstrual age and sex) were identified for CL or Vd.

Conclusion

In this PK study, we characterised the pharmacokinetics of sildenafil in prematurely born infants and found that clearance increases with PNA. Due to the limited sample size in this study, further research in a larger population is needed to extend these findings.

Disclosure(s)

Nothing to disclose
P76 The effect of the pregnancy and lactation labeling rule on prescribing information of FDA-approved drugs
Authors: Patel A , Mazer-Amirshahi M , Fusch G , Chan A , van den Anker J , Samiee-Zafarghandy S
Published: May 2019

Background

The U.S. Food and Drug Administration implemented the new Pregnancy and Lactation Labeling Rule (PLLR) in June 2015. Under PLLR, all new drug applications were to present a narrative risk assessment (as opposed to letter category), while drug approvals after June 2001, were required to phase in by June 2020. The purpose of this study was to assess the quality of presented pregnancy and lactation data in the drug labeling and degree of adherence to the PLLR.

Design/Methods

We reviewed the labeling data of all new molecular entities (NMEs) approved from 1999–2017. The pregnancy and lactation information was classified as: 1. Harmful to use 2. Safe to use 3. Consideration of safety and efficacy. For drugs approvals after June 2001, presence of pregnancy letter category system was noted.

Results

Of the 456 NMEs, 131 (29%) were classified as harmful to use in pregnancy and 207 (45%) as harmful to use during lactation. This number did not follow any specific pattern over the course of 19 years. Less than 1% of drugs were deemed to be safe during pregnancy or lactation. Human data was the source of pregnancy or lactation information for only 2% of drugs. Up to 70% of drugs belonged to each implementation schedule has yet to meet the PLLR compliance requirement.

Conclusion(s)

Pregnant and lactating women are mostly advised against use of medications that might be needed for their health and health of their infants based on very limited data. Pharmaceutical companies lagged behind the required adherence rule for labeling updates on pregnancy and lactation information.

Disclosure(s)

Nothing to disclose
P88 The potential impact of hematocrit correction on evaluation of tacrolimus target exposure in pediatric kidney transplant patients
Authors: Schijvens A , van Hesteren F , Cornelissen M , Bootsma-Robroeks C , Brüggemann R , Burger D , de Wildt S , Schreuder M , ter Heine R
Published: May 2019

Background

Tacrolimus is an important immunosuppressive agent with high intra- and interindividual pharmacokinetic variability and a narrow therapeutic index. As tacrolimus extensively accumulates in erythrocytes, hematocrit is a key factor in the interpretation of tacrolimus whole blood concentrations. However, as hematocrit values in pediatric kidney transplant patients are highly variable after kidney transplantation, translating whole blood concentration targets without taking hematocrit into consideration, is theoretically incorrect. The aim of this study is to evaluate the potential impact of hematocrit correction on tacrolimus target exposure in pediatric kidney transplant patients.

Methods

Data were obtained from 36 pediatric kidney transplant patients. 255 tacrolimus whole blood samples were available, together responsible for 36 area under the concentration time curves (AUCs) and trough concentrations. First, hematocrit-corrected concentrations were derived using a formula describing the relationship between whole blood concentrations, hematocrit, and plasma concentrations. Subsequently, target exposure was evaluated using the converted plasma target concentrations. Ultimately, differences in interpretation of target exposure were identified and evaluated.

Results

In total, 92% of our patients had a lower hematocrit (median 0.29) than the reference value of adult renal transplant patients. A different evaluation of target exposure for either trough level, AUC or both, was defined in 42% of our patients, when applying hematocrit corrected concentrations.

Conclusion

A critical role for hematocrit in therapeutic drug monitoring of tacrolimus in pediatric kidney transplant patients is suggested in this study. Therefore, we believe that hematocrit correction could be a step towards improvement of tacrolimus dose individualization.

Disclosure(s)

All authors declare that they have no conflict of interest. This work was recently accepted for publication in Pediatric Nephrology. We are aware of the statement in the guideline about previously published work, however as we believe that this work suits the aim and topics of the congress very well, we chose to submit this work and will ofcourse leave the final decision to you.
O13 Improved early vancomycin exposure in neonates using a population pharmacokinetic model-based vancomycin dosing regimen
Authors: Smits A , De Saeger E , Vandendriessche A , Cossey V , Allegaert K
Published: May 2019

Background

We previously documented that 2 published vancomycin dosing regimens resulted in subtherapeutic exposure in 66.3 and 76.2% of neonates.1 A new dosing regimen derived from a population pharmacokinetic (PK) analysis and using a loading dose, was implemented in our unit.2 We aimed to investigate if the new regimen results in improved vancomycin exposure (target trough 10–15 mg/L).

Methods

Clinical data and early (24 h after start) vancomycin therapeutic drug monitoring (TDM) in neonates receiving vancomycin for medical reasons, were retrospectively collected and pooled with 2 historical cohorts [cohort 1 (2011, n=193 observations), dosing based on postmenstrual age (PMA) and creatininemia and cohort 2 (2012, n=101 observations), dosing based on PMA and postnatal age (PNA)]. The new regimen [cohort 3 (2018, n=71 observations)] consists of a loading dose, followed by dosing based on birthweight, PNA and ibuprofen co-treatment [2]. Clinical characteristics and early TDM were compared across the cohorts using the Kruskal-Wallis Test. Results were significant if p< 0.05.

Results

Clinical characteristics (cohort 1, 2 and 3 respectively) did not differ significantly across the cohorts. Median (IQ range) GA was 32.8 (28.4–37.6), 32.1 (28.5–37.5), 28 (26–38) weeks with p=0.097; PNA 13 (6–26), 12 (7–23), 14 (10–25) days with p=0.15 and creatininemia 0.43 (0.33–0.55), 0.49 (0.33–0.65), 0.45 (0.32–0.57) mg/dL with p=0.15. Median vancomycin trough level was 7.8 (5.1–11.3), 5.8 (4.1–8.7), 13.3 (9.9–17.3) mg/L with p< 0.0001. With the new regimen, 25.4% of trough levels was < 10 mg/L, 40.8% >15 mg/L, and 33.8% was on target, versus 23.3 and 19.8% on target in cohort 1 and 2 respectively.

Conclusion

A population PK model-based vancomycin dosing regimen using a loading dose, resulted in improved neonatal vancomycin exposure. Although only 25% of trough levels was subtherapeutic, dosing optimalisation for cases with supratherapeutic exposure is also needed, as well as further prospective validation.

References

Vandendriessche, et al. Curr Ther Res Clin Exp 2014.

Janssen, et al. AAC 2015.

Disclosure(s)

Nothing to disclose
P95 Compilation of available plasma renin activity levels in the healthy and cardiac diseased paediatric population
Authors: Suessenbach FK , Gangnus T , Burdman I , Makowski N , Laeer S , Burckhardt BB
Published: May 2019

Background

The physiological and pathophysiological characteristics regarding plasma renin activity (PRA) in the context of the renin-angiotensin-aldosterone-system (RAAS) are well investigated in adults, whereas less is known in paediatric population suffering from heart failure. Challenges in the conduct of paediatric investigations limit the enrolled children often to specific age groups allowing only a partial revaluation of the maturating RAAS. To constitute the comprehensive picture of the paediatric RAAS from 0–18 years, a compilation of available PRA data was conducted via literature search.

Methods

A systematic literature search was accomplished in the context of the ‘Labeling of Enalapril from Neonates up to Adolescence’ (LENA) project in the MEDLINE database via PubMed in January 2019. Key words: plasma renin activity and congenital heart disease/dilative cardiomyopathy/heart failure/congenital heart defect and child/neonate/infant/toddler/paediatric. Eligible records included PRA values in children of 0–18 years of age. Exclusion criteria comprised foetuses, preterm, cord blood, urine, adults, < 2500 g birthweight, ex vivo studies and deviant diseases.

Results

Literature search resulted in 167 findings of which 58 full-text articles were assessed for eligibility. Finally, 33 publications were classified as relevant. Of these, 21 and 12 records were assigned for healthy and cardiac diseased population respectively, leading to PRA data sets of 2000 healthy and 254 diseased children. Visual check of data revealed an age dependent decrease of PRA, in particular in the early childhood, and a substantial elevation of PRA in heart failure patients.

Conclusion

The conducted literature search allowed a systematic description of PRA values in healthy and cardiac diseased paediatrics, which facilitates a classification of reference ranges of the maturing RAAS for LENA and future paediatric trials.

Disclosure(s)

Fabian K. Suessenbach, Tanja Gangnus, Ilja Burdman, Nina Makowski, Stephanie Laeer and Bjoern B Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).