bluuebunny/crossref_metadata_2025 huggingface dataset:
Fecal short‐chain fatty acid concentrations and dysbiosis in dogs with chronic enteropathy
Authors: Minamoto Yasushi , Minamoto Tomomi , Isaiah Anitha , Sattasathuchana Panpicha , Buono Agostino , Rangachari Venkat R. , McNeely Isaac H. , Lidbury Jonathan , Steiner Jörg M. , Suchodolski Jan S.
Published: May 2019

Background

Accumulating evidence shows an important relationship between the gastrointestinal (GI) microbiota and host health. Microbial metabolites are believed to play a critical role in host‐microbial interactions. Short‐chain fatty acids (SCFAs) are major end products of bacterial carbohydrate fermentation in the intestinal tract. Decreased concentrations of SCFAs have been observed in humans with GI disease. However, large‐scale clinical data in dogs are lacking.

Hypothesis/Objective

To evaluate fecal concentrations of SCFAs and the fecal microbiota in healthy control (HC) dogs and dogs with chronic enteropathy (CE).

Animals

Forty‐nine privately owned HC dogs and 73 dogs with CE.

Methods

Prospective cohort study. Fecal concentrations of SCFAs were measured using gas chromatography/mass spectrometry. Illumina sequencing and quantitative real‐time polymerase chain reaction were utilized to evaluate the fecal microbiota.

Results

Fecal concentrations (median [range] μmol/g of dry matter) of acetate were lower (P = .03) in dogs with CE (185.8 [20.1‐1042.1]) than in HC dogs (224.0 [87.7‐672.8]). Propionate were also lower (P < .001) in dogs with CE (46.4 [0.4‐227.9]) than in HC dogs (105.9 [1.6‐266.9]). Moreover, total SCFAs were lower (P = .005) in dogs with CE (268.1 [21.8‐1378.2]) than in HC dogs (377.2 [126.6‐927.0]). Dysbiosis in dogs with CE was characterized by decreased bacterial diversity and richness, distinct microbial community clustering compared with that in HC dogs, and a higher dysbiosis index.

Conclusions and Clinical Importance

Dogs with CE had an altered fecal SCFA concentration accompanied by significant changes of the fecal microbiota.
RCEP and Trans‐Pacific Intellectual Property Norms: Implications for India
Authors: Sharma Seemantani
Published: May 2019

This paper examines the Regional Comprehensive Economic Partnership agreement (RCEP) with a focus on the intellectual property norms which it seeks to develop in the context of India. It specifically analyses the key provisions of the leaked IP chapter and its implications for India's IP regime. The paper posits that India should not oppose the draft IP chapter merely on grounds of its TRIPS‐plus nature in order to adhere to the “minimum standards treaty” principle of the TRIPS Agreement. The conclusion allays the concerns of the civil society which has opposed the draft IP chapter merely on grounds of its TRIPS‐plus nature.
Analysis of Merger Control in a Network Products Market
Authors: Toshimitsu Tsuyoshi
Published: May 2019

Using a horizontally differentiated three‐firm model, we consider horizontal mergers and antitrust policy in a network products market, where network externalities and compatibilities between products and services are observed. In particular, we focus on the role of merger‐related network compatibility. That is, if the degree of the net degree of merger‐related network compatibility is larger than the degree of product substitutability, consumer surplus is higher than in the premerger case. In this case, the proposed merger is allowed by antitrust authorities based on a consumer welfare standard. Furthermore, relating to a merger externality on an outsider, we examine the American Online and Time Warner case.
The pathogenic actinobacterium Rhodococcus equi: what's in a name?
Authors: Vázquez‐Boland José A. , Meijer Wim G.
Published: May 2019

Rhodococcus equi is the only recognized animal pathogenic species within an extended genus of metabolically versatile Actinobacteria of considerable biotechnological interest. Best known as a horse pathogen, R. equi is commonly isolated from other animal species, particularly pigs and ruminants, and causes severe opportunistic infections in people. As typical in the rhodococci, R. equi niche specialization is extrachromosomally determined, via a conjugative virulence plasmid that promotes intramacrophage survival. Progress in the molecular understanding of R. equi and its recent rise as a novel paradigm of multihost adaptation has been accompanied by an unusual nomenclatural instability, with a confusing succession of names: "Prescottia equi", "Prescotella equi", Corynebacterium hoagii and Rhodococcus hoagii. This article reviews current advances in the genomics, biology and virulence of this pathogenic actinobacterium with a unique mechanism of plasmid‐transferable animal host tropism. It also discusses the taxonomic and nomenclatural issues around R. equi in the light of recent phylogenomic evidence that confirms its membership as a bona fide Rhodococcus.
Job's Unfinalizable Voice: An Addendum to David Burrell's Deconstructing Theodicy
Authors: Williams Trevor B
Published: May 2019

Modern theodicies often offer definitive explanations for the unsolvable problem of human suffering. This philosophical enterprise was challenged by David B. Burrell's book,Deconstructing Theodicy: Why Job Has Nothing to Say to the Puzzle of Suffering(2008). His observations about the book of Job and the way it militates against theodical speculation are compelling, but there is a missed opportunity with his exegesis of Job 42:6. The Hebrew of Job's last words can be translated in at least five distinct (and legitimate) ways. Using this grammatical characteristic, this paper argues that the ambiguity in 42:6 creates an “unfinalizable” quality that allows sufferers to be unsilenced and participate in the meaning-making process. Situating the addendum with philosophical ruminations on theodicy, the argument turns to an exegetical section that comments on Burrell's discussion in “Denouement and Epilogue” and analyzes the Hebrew grammar of Job 42:1-6. This addendum compliments Burrell's deconstruction of theodicy, adding a further pool of resources for sufferers to remain unsilenced and narrate their own questioning of God.
Increased food utilization indices and decreased proteolytic activity in Helicoverpa armigera larvae fed sublethal Bacillus thuringiensis‐treated diet
Authors: Fathipour Yaghoub , Sedaratian Amin , Bagheri Abdoolnabi , Talaei‐Hassanlouei Reza
Published: May 2019

The cotton bollworm Helicoverpa armigera is one of the most devastating insect pests. A set of protease enzymes allows this species to feed on different host plant species. Control measures in agriculture often involve the application of the pathogenic bacterium Bacillus thuringiensis subsp. kurstaki (Btk). In the present study, the effects of sublethal Btk doses are evaluated with respect to the food utilization indices and proteolytic activities of Helicoverpa armigera. Accordingly, the H. armigera larvae are fed with artificial diet containing sublethal Btk doses (LC5, LC10, LC15, LC20 and LC25) and a Btk‐free diet as control. All but one of the food utilization indices we measured is observed to increase significantly with increasing Btk doses. By contrast, the specific activity of total protease, chymotrypsin and elastase enzymes decrease significantly with an increasing Btk concentration. We conclude that Btk was not toxic to H. armigera larvae and any damage that it causes can be compensated for by H. armigera larvae via various mechanisms. In conclusion, increased nutritional indices in the larvae fed with Btk diet represent an important issue that needs to be considered to avoid the pest establishing Bt resistant populations. Meanwhile, the lack of effect of Btk sublethal concentrations on trypsin enzyme specific activity can bolster this challenge.
Promoting Children Growth and Development: A community‐based cluster randomized controlled trial in rural areas of Indonesia
Authors: Susanto Tantut , Yunanto Rismawan Adi , Rasny Hanny , Susumaningrum Latifa Aini , Nur Kholid Rosyidi Muhammad
Published: May 2019

Objective

This study examined the influence of the Promote Children's Growth and Development (PCGD) intervention on children's growth and development in rural areas in Indonesia.

Design and Sample

A community‐based nonblinded cluster randomized controlled trial was conducted. Twelve clusters of villages were matched based on population and randomly assigned to intervention group (six clusters and 72 caregivers dyads) or control group (six clusters and 72 caregivers dyads) with inclusion criteria age 0–72 months and attending integrated health centers (Posyandu). The intervention was conducted for 14 weeks with caregivers.

Measures

The weight‐for‐age Z‐score (WAZ), height‐for‐age Z‐score (HAZ), weight‐for‐height Z‐score (WHZ), and body mass index‐for‐age Z‐score (BAZ) were calculated using World Health Organization Anthro‐Plus version 1.0.3. A prescreening developmental questionnaire (PSDQ) measured the development of children before and after the intervention.

Results

The proportion of stunting of HAZ, wasting of WHZ, and deviation development of PSDQ were higher in the control group compared to the intervention group, respectively (22.2% vs. 37.5%), (9.7% vs. 4.2%), and (12.5% vs. 2.8%). Caregivers were more confident promoting children's growth and development after attending 12 sessions of the PCGD intervention.

Conclusion

The 12 session PCGD intervention is effective for promoting the growth and development of children of 0–72 months. The PCGD could be considered for implementation in community health centers.
The Missing Links: Choosing and Rejecting International Issue Linkages in the Presidential Interest
Authors: Musgrave Paul
Published: May 2019

Why do presidents link issues in some international negotiations but not others? Existing explanations stress the value of linkage to negotiating states, the role of interest groups, and the costs of linking. I argue that issue linkage can be driven by prospective benefits for the negotiator. In the context of U.S. negotiating practices, presidents will press for issue linkage in their own interests. Using archival documents and taped conversations, I demonstrate that presidential interest dictated U.S. adoption or rejection of linkage between economics and security during the Nixon administration's quest to secure voluntary export restrictions on textiles from Japan, Hong Kong, South Korea, and Taiwan during 1969–71.
Perceptual Bias and Public Programs: The Case of the United States and Hospital Care
Authors: Meier Kenneth J. , Johnson Austin P. , An Seung‐Ho
Published: May 2019

This article examines whether the public holds biased perceptions of public organizations (in this case, hospitals) in the United States and whether organizations get credit for positive results from program evaluations. Using an experimental design that replicates Hvidman and Andersen's2016Danish study, the study finds no negative public sector biases in the United States, but organizations are not given any credit for positive program evaluations. These results hold in two experimental replications. The implications of the findings for the measurement of public perceptions of government programs and for effective democratic governance are discussed.
Discovery of an HLA‐C*03:03:01:01 variant, HLA‐C*03:03:54, in a Taiwanese individual
Authors: Yang Kuo‐Liang , Lin Py‐Yu
Published: May 2019

One nucleotide substitution in codon 223 of HLA‐C*03:03:01:01 results in a novel allele, HLA‐C*03:03:54.
Identification of the new HLA‐C*16:02:17 allele in a Brazilian candidate donor for bone marrow donation
Authors: Stelet Vinicius , Cita Rafael , Romero Matilde , Mendes Maristela , Binato Renata
Published: May 2019

Identification of the novel HLA‐C*16:02:17 allele that differs from HLA‐C*16:02:01 in exon 2.
Developing and testing prognostic bio‐scoring systems for canine mammary gland carcinomas
Authors: Sorenmo Karin U. , Durham Amy C. , Kristiansen Veronica , Pena Laura , Goldschmidt Michael H. , Stefanovski Darko
Published: May 2019

Canine mammary carcinomas (CMC) represent a range of histolopathological subtypes with diverse biological behaviours. Several individual factors, including stage, grade, subtypes and presence of invasion, predict outcome. Less is known how these factors interact and impact prognosis. The purpose of this work was to develop and test comprehensive bio‐scoring systems in CMCs. Clinical and histopathological data from 127 dogs with MCs treated through two prospective studies were obtained. All dogs underwent standardized pre‐surgical staging, treatments and regular follow‐up visits. All tumours were evaluated, classified and graded according to published guidelines. Time to primary metastasis was the main endpoint in this study. Two bio‐scoring systems were developed: The multivariate scoring (MVS) was based on traditional statistical analysis where only factors significant in the multivariate analysis (tumour size and grade) were kept for the final model. The refined flexible scoring (RFS) system was based on results from subgroup analysis, which guided the development of a flexible system. Progressive worsening prognosis was observed with increasing bio‐scores in both systems. MVS: Median primary metastasis‐free survival (TTM1 days) was not reached in dogs with bio‐scores 0 to 5, 10, 15 and 648, 149, 317, in MVS groups 25, 30, 40, respectively. Similarly, TTM1 was not reached in dogs with RFS 0, 1, 2 and 374, 407 and 149, in dogs with bio‐scores 3, 4, 5, respectively. However, a more distinct separation between dogs with high risk vs low risk for metastasis was observed with RFS, suggesting superior overall prognostication regarding the risk for metastasis.
The effects of topical dorzolamide 2% and brinzolamide 1%, either alone or combined with timolol 0.5%, on intraocular pressure, pupil diameter, and heart rate in healthy cats
Authors: Slenter Inge J. M. , Djajadiningrat‐Laanen Sylvia C. , Elders Daphne J. , de Gee Reinoud , Koele Linda E. , Vermeer Loes W. , Boevé Michael H.
Published: May 2019

Objective

To investigate the effects of topical dorzolamide 2% q8h and brinzolamide 1% q8h, administered either alone (A and B, respectively) or in combination with topical timolol 0.5% q12h (C and D, respectively), on the circadian pattern of intraocular pressure (IOP), the pupil size, and heart rate in healthy cats.

Methods

In this prospective, randomized, double‐blinded study, 10 healthy, adult cats were randomly assigned to one of four groups and the eye to be medicated was randomly assigned. IOP, pupil diameter, and heart rate were measured at 3‐hour intervals. A 5 days’ adjustment period was followed by a 5 days’ placebo (baseline) period. Then, all groups of cats received all four treatments (A‐D) according to a Latin square‐based rotating schedule. Five days’ medication periods were alternated with 3 days’ washout periods.

Results

Mean baseline IOP was 13.6 ± 2.7 mm Hg. All treatments resulted in a statistically significant decrease in mean IOP in the treated eye: A: −2.33 mm Hg (95% CI: −2.71, −1.94), B: −1.91 mm Hg (95% CI: −2.30, −1.53), C: −2.36 mm Hg (95% CI: −2.74, −1.97), and D: −2.37 mm Hg (95% CI: −2.76, −1.98) and the nontreated eye: A: −0.19 mm Hg (95% CI: −0.28, −0.11), B: −0.18 mm Hg (95% CI: −0.27, −0.10), C −0.31 mm Hg (95% CI: −0.40, −0.23), and D: −0.24 mm Hg (95% CI: −0.32, −0.15). Timolol resulted in an additional, significant decrease in IOP of 4% and 5%, respectively, compared to A and B, and in mild bradycardia and miosis.

Conclusions

Topical administration of dorzolamide 2% and brinzolamide 1% q8h significantly decreased IOP in healthy cats. Supplemental timolol 0.5% eye drops q12h resulted in an additional, statistically significant reduction of IOP.
A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection
Authors: Kose Nurgun , Fox Julie M. , Sapparapu Gopal , Bombardi Robin , Tennekoon Rashika N. , de Silva A. Dharshan , Elbashir Sayda M. , Theisen Matthew A. , Humphris-Narayanan Elisabeth , Ciaramella Giuseppe , Himansu Sunny , Diamond Michael S. , Crowe James E.
Published: May 2019

Lipid nanoparticles containing mRNA encoding a human antibody for chikungunya virus protect against infection and arthritis.
P62 Population pharmacokinetic study of aminophylline in Indian preterm neonates (≤34weeks) with apnoea; a longitudinal observational study
Authors: M S , Lewis L , Mallayasamy S
Published: May 2019

Background

Current dosage regimen of aminophylline is similar in both Appropriate for Gestational Age (AGA) and Small for Gestational Age (SGA) preterm neonates.1 In contrast with AGA babies, SGA babies handle drugs in different way. However, developing countries like India has significant proportion of Growth Restricted/SGA babies. Hence, there is a need to develop appropriate dosage regimen in this population. Objective of the current study was set to develop and qualify the Population-Pharmacokinetic (PPK) model for aminophylline in premature neonates in Indian population.2

Methods

Aminophylline-treated neonates with IV loading dose of 5 mg/kg followed by maintenance dose of 1.5 or 2 mg/kg 8th hourly for Apnoea of Prematurity (AOP) were included. Any other conditions for secondary causes were excluded. Blood samples were collected by adopting sparse sample scheme and estimated by LCMS-MS. PPK model was developed with appropriate covariates.3 Data was analysed by NONMEM vesion 7.3. Non-parametric bootstrap procedure and Visual Predictive Check (VPC) was used to qualify the developed model.

Results

One compartment, first-order structured model was fitted to the dataset containing 454 observations from 107 neonates. PPK parameters were represented as model estimated values and variability was depicted as% Co-efficient of variation (%CV). Typical population value of CL was 0.011 L/hour with inter-individual variability (IIV) of 59% and V was 0.332 (L/kg) with 31% IIV. Residual error was found to be 19%. Only postnatal age (PNA) had significant effect on V which was assessed by forward addition and backword elimination regression model.

Conclusion

AGA and SGA had no influence on PK parameters. However, PNA showed to have significant influence on V. Developed nomogram based on the qualified model may be effective and safe for aminophylline therapy in preterm neonates with apnoea.

References

Shivakumar M, Jayashree P, Najih M, Lewis LES, Bhat Y R, Kamath A, et al. Comparative Efficacy and Safety of Caffeine and Aminophylline for Apnea of Prematurity in Preterm (≤34 weeks) Neonates: A Randomized Controlled Trial. Indian Pediatr 2017 Apr 15;54(4):279–83.

U S Department of Health and Human Services, FDA, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER): Guidance for Industry Population pharmacokinetics; 1991; Feb CP1, 35 pages.

Ette EI, Sun H, Ludden TM, Balanced designs in longitudinal Population Pharmacokinetic studies. Journal of Clinical Pharmacology 1998 May; 38(5):417–423.

Disclosure(s)

Nothing to disclose
P68 Significant oral drug use in critically ill children: rational therapy or a black box?
Authors: Mooij M , Windster J , van Rosmalen J , Hanff L , Tibboel D , de Wildt S
Published: May 2019

Background

The disposition of orally prescribed drugs in critically ill children may be affected critical illness in in addition to age, resulting in erratic effects and safety. We aimed to study oral drug prescribing in the neonatal and pediatric intensive care unit (NICU and PICU).

Methods

A one-year retrospective cohort study of all drug prescriptions, including route of administration for all children admitted to the NICU and PICU of the Erasmus MC-Sophia’s children’s hospital.

Results

1723 children with 2091 unique admissions received per admission (median [IQR]) 5 (3–10) drugs; 1 (0–2) orally and 3 (1–7) intravenously (IV). During mechanical ventilation 15% and 75% of drugs were given orally and IV, respectively. In non-ventilated patients, 27% of drugs were given orally and 60% IV. The 5 most frequently orally prescribed drugs were: vitamin K, spironolactone, oral probiotics, amphotericin B (prophylaxis) and trimethoprim.

Discussion

Critically ill infants receive a considerable proportion of drugs orally. Considering that critical illness may significantly impact intestinal drug absorption, this may expose them to an increased risk of ineffective or unsafe drug therapy.

Disclosure(s)

Nothing to disclose
P74 Rituximab effect on B cell depletion in paediatric patients with autoimmune diseases: a retrospective dose-response analysis of an observational study
Authors: Pan S , Yu H , Surti A , Cheng I , Marks SD , Brogan PA , Eleftheriou D , Standing JF
Published: May 2019

Background

Rituximab is a chimeric IgG1 monoclonal antibody that depletes B cells for the treatment of several conditions including autoimmune diseases. It is not licensed for use in children but administered off-label. This study aimed to quantify the effect of rituximab on B cell depletion in children with autoimmune diseases and to optimise the dosing regimen.

Methods

Electronic health record data were collected from a retrospective and anonymised study at Great Ormond Street Hospital in London. Dosing protocols of rituximab were two 750 mg/m2 intravenous infusions or four weekly 375 mg/m2 infusions. Serum concentrations of rituximab were not measured. CD19+ lymphocyte counts were taken before and after rituximab treatment. A turnover mechanism described the life cycle of CD19+ lymphocytes with rituximab increasing the death rate of CD19+ lymphocytes; a negative feedback was added on the production rate to examine the rebound effect. Rituximab was assumed to decay by first-order kinetics.

Results

258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The dose-response model well described the time course of CD19+ lymphocytes following rituximab administration. The elimination half-lives of rituximab and CD19+ lymphocytes were estimated to be 19 and 35 days, respectively, consistent with findings from other studies [1–5]. The rebound increase in CD19+ lymphocytes was found negligible. Methotrexate and cyclophosphamide increased the maximum death rate by 66% and 38% respectively. Age and gender were not significant covariates.

Simulations from the model suggested that a single infusion of rituximab of 375 mg/m2 can provide similar six-month suppression of CD19+ lymphocytes to the higher doses currently used. Methotrexate or cyclophosphamide added minimal suppression effect on CD19+ lymphocytes when taken concurrently with rituximab.

Conclusions

Our results could be used in future to assess the effect of rituximab biosimilars and to inform biosimilar dosing in paediatric populations.

References

Ng, et al. J Clin Pharmacol. 2005; 45:792–801

Li, et al. Blood. 2007; 110:2371

Li, et al. J Clin Pharmacol. 2012; 52:1918–26

Fulcher and Basten. Immunol Cell Biol. 1997; 75:446–55

Macallan, et al. Blood. 2005; 105:3633–40

Disclosure(s)

Nothing to disclose
P78 Pharmacokinetics of intravenous and intranasal nalbuphine in infants
Authors: Pfiffner M , Gotta V , Berger-Olah E , Pfister M , Vonbach P
Published: May 2019

Background

Nalbuphine is a mixed agonist-antagonist opioid analgesic agent frequently used in paediatrics, and licensed for parenteral use only. Intranasal delivery could be a safe, effective and non-invasive alternative, especially in infants in the acute setting. However, pharmacokinetic (PK) data for this route of administration is completely lacking. The aim of this study was to assess PK of nalbuphine in infants 1–3 months after single intravenous (0.05 mg/kg) and intranasal (0.1 mg/kg) application, respectively.

Methods

We conducted a prospective, single centre, open-label pharmacokinetic study in infants 1–3 months undergoing sepsis workup in the emergency unit. Included infants received alternating nalbuphine as 0.05 mg/kg intravenous bolus or as 0.1 mg/kg intranasal spray. PK samples were taken at 3 pre-defined time points (15, 30 and max. 240 min post-dose before discharge). Area under the concentration-time curve (AUC0-Tlast, and AUC0-infinity for i.v.) was calculated using noncompartmental analysis and was compared between groups using Wilcoxon test. Further parameters derived included maximum concentration (Cmax), time of maximum concentration (Tmax for i.n.) and terminal half-life (t1/2).

Results

A total of 31 patients were included in the analysis. Median age was 55 days [interquartile range 38–63] in the intranasal (N=20) and 42 [37–76] days in the iv group (N=11). Median AUC0-Tlast was 7.6 (5.4–10.4) mcg*h/L following intranasal versus 7.9 (6.0–14.7) mcg*h/L for iv administration (p=0.46). AUC0-Tlast (i.v.) covered 80 [68–83]% of AUC0-infinity. Median Cmax was 4.5 [3.5–5.6] mcg/L (i.n.) versus 6.5 [5.3–15.9] mcg/L (i.v.) (p=0.014), t1/22.4 [1.3–2.8] h (i.n.) versus 1.3 [1.1–1.5] h (i.v.) (p=0.021). Tmax occurred 37 [32–65] min after intranasal administration.

Conclusion

This first PK study of intranasal nalbuphine in infants suggests that 0.1 mg/kg i.n. dosing provides similar exposure as 0.05 mg/kg i.v. in infants in terms of AUC, and hence intranasal bioavailability close to 50%.

Disclosure(s)

Nothing to disclose
P81 Use of systemic antibiotics in Austrian children and adolescents: a survey
Authors: Rauch E , Lagler FB , Herkner H , Strenger V , Male C
Published: May 2019

Background

Several surveys that have assessed the use of antibiotic medicines for children and adolescents demonstrate significant heterogeneity in prescription patterns between different countries. The liberal use of antibacterial treatment, particularly unjustified use of broad spectrum antibiotics, is one of the main reasons for increasing rates of antibiotic resistance. We have studied antibiotics prescription frequencies in children and adolescents in Austria covering both primary and hospital care settings, in order to obtain a representative survey for our country.

Methods

Prescription data for systemic antibiotics were assessed for the year 2014. For primary care, reimbursement data were obtained from Austrian health insurances. For hospital care, information on medicines dispensed to paediatric wards was obtained from hospital pharmacies. Frequencies of systemic antibiotic use were analyzed by Anatomical Therapeutic Chemical classification system, age groups, care setting, and in relation to all other medicines used. Systemic antibiotics were divided into subgroups, like broad and narrow spectrum penicillins, cephalosporins, tetracyclins, and others.

Results

Systemic antibiotics comprised 24% and 21% of all medicines prescribed to children and adolescents in primary care and hospital care, respectively. The most frequent were broad spectrum antibiotics (32% and 35% of systemic antibiotics prescribed) in both primary and hospital care settings. Macrolides and 2nd generation cephalosporins were more frequently prescribed in primary care setting, whereas ß-lactam antibiotics other than cephalosporins and antibiotics, such as fluorochinolones, aminoglycosides, or linezolid were more frequently used in hospital.

Conclusions

This is the first representative survey investigating the use of systemic antibiotics in children and adolescents in Austria. The study allows comparison of prescription patterns to other European countries: it reveals rather big differences to systemic antibiotics prescription in Italy, the Netherlands and Denmark, whereas prescription patterns are similar in Germany and Austria. Furthermore, this survey provides the basis to assess temporal trends in the future.

Disclosure(s)

Nothing to disclose
O12 Circulating concentrations of broad-spectrum beta-lactams in children with cancer: beware of glomerular hyperfiltration!
Authors: André P , Diezi L , Decosterd LA , Crisinel PA , Dao K , Diezi M , Asner S , Buclin T
Published: May 2019

Background

Broad-spectrum beta-lactams such as meropenem (MER) and piperacillin-tazobactam (PIP) are commonly prescribed in children with cancer having febrile neutropenia. They are introduced at intensive dosage, unless decreased renal function calls for dose reduction. Recently, glomerular hyperfiltration (HF) was recognized to be frequent among children with cancer during initial cycles of chemotherapy.1 We evaluated the impact of HF on therapeutic exposure to MER and PIP.

Methods

We retrieved retrospectively all MER and PIP plasma levels measured in children with cancer in our hospital between 2012 and 2018. We compared trough levels with usual therapeutic ranges (derived from reference values of minimum inhibitory concentrations). We classified the children according to plasma creatinine and estimated glomerular filtration rate (Schwartz formula) as either altered-normal (< 160 mL/min/1.73 m2) or increased (i.e. HF, ≥160). Neutropenia was defined as absolute neutrophil count < 500 cells/µL.

Results

We collected 120 concentration values (53 MER, 67 PIP) measured in 50 children with cancer. Among them, 74 (62%) had concomitant creatinine values suggestive of HF, and 80 (67%) were neutropenic. Overall, 67% of trough levels were below usual therapeutic ranges (MER: 2–8 mg/L, PIP 8–30 mg/L). This was more often the case in presence of concomitant HF (MER: 92%, PIP: 83%), often associated with neutropenia. Low exposure was observed not only at initial intensive dosage (MER: 120 mg/kg/day, PIP: 400 mg/kg/day)2 but tended to persist despite dosage readjustment based on concentration monitoring. Moreover, bacteremia was diagnosed in 38 cases.

Conclusion

Current recommended doses of MER and PIP do not provide optimal concentration coverage throughout the dosing interval in a large fraction of children with cancer and febrile neutropenia as a result of HF. Monitoring of beta-lactams should be offered to all children with cancer to ensure best therapeutic success and avoid the development of resistance.

References

Kwatra NS, Meany HJ, Ghelani SJ, Zahavi D, Pandya N, Majd M. Glomerular hyperfiltration in children with cancer: prevalence and a hypothesis. Pediatr Radiol 2017;47(2):221–226.

The Lexicomp Pediatric & Neonatal Dosage Handbook, 21st edition, Lexicomp, USA.

Disclosure(s)

Nothing to disclose
P87 The Swiss Association of Perinatal Pharmacology, SAPP: goals
Authors: Schenkel L , von Mandach U ,   The Editorial Board of the SAPP
Published: May 2019

Background

The medicine of pregnant women practices to a targeted personalized approach, tailored to the specific characteristics and needs the implications of interdisciplinary work between healthcare stakeholders. Perinatal pharmacology comprises the impact of substances (drugs, medications and others) in pregnant women, nursing mothers, the unborn child, the premature, the newborn baby and the breastfed baby. Most of the drugs are off-label used. In this field grand challenge for Frontiers in Medicine emphasizes the importance of translational medicine.

Aim

The primary goal of SAPP has always been and remains the same: it is the link between medicine and pharmacy, between practice, clinic, research and health authorities, in order to increase the safety of medicines in the population of pregnant and breastfeeding women and their newborns.1

Methods

On December 6, 2007, an interdisciplinary team of 8 physicians and pharmacists founded the Swiss Association of Perinatal Pharmacology, SAPP. It collects and promotes new findings in the field of perinatal pharmacology.

Results

Specialists from all areas of perinatal pharmacology work together in a scientific committee to develop and update evidence-based principles for work in everyday clinical practice (hospitals, doctor´s surgeries, pharmacies). Today, around 200 members benefit from this, who can orient themselves in regular further training courses and basic documents (monographs of active substances, therapy recommendations based on original literature). The SAPP thus closes the gap resulting from the predominant off-label use and the resulting lack of information on drugs in this population.

Conclusion

The primary objective of SAPP has been achieved - it provides guidance for the practioners in the broad field of perinatal pharmacology and bridges the gap caused by the lack of drug approvals in this population. Long-term survival will be ensured by measures anchored in law.

Reference

www.sappinfo.ch

Disclosure(s)

Nothing to disclose
P89 Emicizumab development in paediatric patients with congenital hemophilia A and inhibitors against factor VIII
Authors: Schmitt C , Yoneyama K , Chang T , Retout S , Grimm H -P , Levy GG
Published: May 2019

Background

Emicizumab, a bispecific monoclonal antibody, bridges activated factor (F) IX (FIXa) and FX, restoring missing FVIIIa function in patients with hemophilia A (PwHA). It has been recently approved for routine prophylaxis of bleeding episodes in PwHA with FVIII inhibitors in all age groups. We herein describe the paediatric development of emicizumab with a focus on dose selection, study design and extrapolation of efficacy.

Methods

The dosing regimen for the HAVEN 1 study (adolescents/adults) was selected based on the exposure-response (annualized bleeding rate [ABR]) relationship derived from a phase I/II study in adolescent/adult PwHA. Pharmacokinetic (PK) simulations, with or without maturation of clearance (CL MAT), were performed to guide selection of the dosing regimen for the HAVEN 2 study (paediatrics) aiming to achieve the same target exposure as in HAVEN 1. HAVEN 2 employed a flexible design with possibility for individual- and population-level dose up-titration. Additional PK modeling and simulations together with exposure-response analyses were used to support full extrapolation of efficacy in any age category where no data was available.

Results

1.5 mg/kg/week in HAVEN 1 provided mean trough concentrations of ∼50 µg/mL and was associated with a 87% reduction in ABR. Doses of ≥ 1.5 (with CL MAT) and ≥ 2.25 mg/kg/week (without CL MAT) were predicted to achieve this target exposure in children. HAVEN 2 began by investigating the same dose as HAVEN 1. Similar trough concentrations of ∼ 50 µg/mL were achieved in children and were associated with low ABR. No patients < 1 year were enrolled in HAVEN 2. PK simulations and pharmacological rationale suggested that a different dose for these patients was not warranted.

Conclusions

Efficacy of emicizumab in adolescents/adults was demonstrated in HAVEN 1, partially extrapolated to HAVEN 2 participants 1–11 year of age, and fully extrapolated in patients < 1 year.

Disclosure(s)

Authors are Roche/Genentech employees
P91 Real-time breath analysis of antiepileptic drugs
Authors: Singh KD , Ziesenitz V , Usemann J , Frey U , van den Anker J , Datta A , Sinues P
Published: May 2019

Background

In the field of medicine, serum concentrations of drugs with a narrow therapeutic window, used to treat seizures, are measured to assure the most efficacious and safe way of treating every individual patient. This form of personalised medicine is called therapeutic drug monitoring (TDM). We have explored the possibility to measure and monitor drugs in exhaled breath (EB), to perform completely painless and non-invasive TDM for a future clinical application especially in pediatric patients.

Methods

We employed secondary electrospray ionisation in combination with high resolution mass spectrometry to obtain highly resolved EB mass spectra. We then statistically compared these EB mass spectra between patients taking antiepileptic drugs against controls (no drugs), to find potential EB-based bio-markers for drugs. Suspected drug metabolites detected in breath will be compared with systemic blood concentrations. We will screen a total of 15 drugs requiring TDM.

Results

So far we have successfully measured EB mass spectra of patients undergoing treatment with Valproic acid (VPA, n = 27), Lamotrigine (n = 19), Levetiracetam (n = 15) and Oxcarbazepine (n = 11). Exploratory data analyses are still ongoing for these drugs. However, for VPA we have identified few candidate ions which enables us to predict free VPA blood concentrations (RMSE 1.5 mg/L). Additionally, we have positively identify two molecules involved in free VPA prediction, based on LC-MS/MS of the exhaled breath condensate. In the near future we will continue to perform data analyses and LC-MS/MS on ions of interest to confirm their identity.

Conclusions

This work is a part of an ongoing study and it is too early to come up with a definite conclusion. However, we observed several differentially abundant ions between controls and epileptic patients for various drugs, but the identity and clinical significance of these ions is yet to be determined.

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. VZ and JV are supported by the Eckenstein-Geigy Foundation. *AD and PS: shared senior authorship.
P92 Metabolomics in children with heart failure using ACE-inhibitors, an exciting opportunity?
Authors: Smeets N , Dalinghaus M , de Wildt S
Published: May 2019

Introduction

ACE inhibitors (ACEi) have a prominent place in the treatment of heart failure in children. However, there is a significant interpatient variability in efficacy and safety in those children that is not completely understood. Metabolomics provides an interesting innovative approach to better understand underlying mechanisms for variation in disease and response to therapy. With this review, we aim to provide an overview of metabolomics in the field of heart failure therapy with or without ACEi in both adults and children and try to identify gaps in this field.

Methods

The PubMed database was systematically searched using several search strategies. Articles were labelled as relevant when they included information on either metabolomics of adult patients with heart failure and/or ACEi-therapy or in children. This yielded 42 relevant articles

Results

24 articles were found describing metabolomics in adults with heart failure, either with or without ACEi-therapy. In addition, several metabolites were identified in adults correlating with either ACEi-efficacy or safety. No metabolomics articles were found in children with heart failure or in children on ACEi-therapy. Several papers (18) were found on metabolomics in children for other diseases and/or treatments.

Conclusion

Metabolomics in adult heart failure patients has helped to unravel part of observed disease and therapy variability, and appears helpful in identifying patients at risk for therapy failure as well as detecting novel targets for heart failure therapy. In children, a significant information gap exists. This provides exciting opportunities for personalized treatment of heart failure.

Disclosure(s)

This work was partially supported by LENA, a Collaborative Project funded by the European Union under the 7th Framework Programme under grant agreement n° 602295.
P93 Semi-mechanistic modelling of hydrocortisone pharmacokinetics in paediatric patients with adrenal insufficiency
Authors: Stachanow V , Melin J , Michelet R , Blankenstein O , Neumann U , Ross R , Whitaker M , Huisinga W , Kloft C
Published: May 2019

Background

Patients with congenital adrenal hyperplasia (CAH) have low to no biosynthesis of cortisol and require lifelong cortisol replacement. Optimisation of hydrocortisone (HC, synthetic cortisol) therapy in this population is important, since too low or high cortisol concentrations increase the risk of adrenal crisis or Cushing’s syndrome1. HC has nonlinear pharmacokinetics (PK) caused by saturable binding to corticosteroid binding globulin (CBG)2. The objective of this analysis was to extend an established paediatric HC PK-model3 with dried blood spot (DBS) data in order to further characterise the binding behaviour of HC in children.

Methods

A semi-mechanistic adult PK model for a novel HC formulation4 has previously been reduced to a paediatric model using sparse plasma samples from a phase III study in 24 patients with adrenal insufficiency5. Plasma and DBS concentrations of cortisol were collected and additional DBS HC concentrations were obtained from a follow-up study. The relation between plasma and DBS samples was characterised by a graphical evaluation, after which nonlinear mixed-effects modelling was applied using NONMEM 7.4.

Results

Plasma concentrations of cortisol were substantially higher than the corresponding DBS concentrations. The plasma/DBS ratio ranged between 2 to 8 within and between children, while the relation between the cortisol DBS concentrations and cortisol plasma concentrations showed nonlinear behaviour mirroring the nonlinear binding kinetics to CBG.

Conclusions

Our graphical analysis identified substantial differences and high inter- and intraindividual variabilities between plasma and DBS samples. A nonlinear mixed-effects model is being set up to quantify these findings and allow for further prediction of HC exposure. Afterwards, effect biomarkers can be included in order to evaluate cortisol replacement therapy and to optimise the HC treatment in paediatric patients.

References

Speiser PW, et al. J Clin Endocrinol Metab 2010;95(9):4133–4160.

Lentjes EG, WM, et al:J Clin Endocrinol Metab. 1999;84(2):682–687.

Melin J:Dissertation 2017.

Melin J, et al:Clin Pharmacokinet. 2018;57(4):515–527.

Neumann U. et al:Clin Endocrinol. 2018;88(1):21–29.

Disclosure(s)

Nothing to disclose
P101 Extending the Dutch Paediatric Formulary across Europe: successful development of country specific, parallel, paediatric drug formularies
Authors: Van der Zanden T , Neubert A , Zahn J , Wimmer S , de Hoop M , Rosness T , Kjeldby-Høie C , Teigen A , Male C , Rauch E , Lagler F , Rascher W , de Wildt S
Published: May 2019

Backgrounds

As many drugs in paediatrics are used of off-label, prescribers across Europe face a lack of evidence-based dosing guidelines. The Dutch Paediatric Formulary (DPF) was developed to provide dosing guidelines based on best available evidence from registration data, investigator-initiated research, clinical experience and consensus (1). The DPF has recently joined forces with Germany, Norway and Austria aiming to develop multi-language, parallel, paediatric drug formularies based on the DPF.

Methods

The DPF database and ICT framework were extended to a duplicate database for Germany. The dosing guidelines were translated to German and reviewed for fit with German practice. Relevant drugs and dosing recommendations were selected and country-specific information was added to address country-specific needs. Work-sharing on content development was studied in a small pilot.

Results

The German Pediatric Formulary (www.kinderformularium.de) was launched on 1 October 2018 within a German paediatric medication safety project (KiDSafe). At that time 119 of 769 drugs were reviewed and published in the German formulary.The dosing recommendations of the DPF show a good fit with German practice; i.e. adaptations were needed in less than 10% of the cases caused by differences in licensing status, national guidelines or availability of formulations. There were no differences in interpretation of evidence. Nine drugs - highly relevant for German practice, but not listed in the DPF, were added to the German formulary based on SmPC. The content work sharing was piloted by the development of a new monograph and the periodic revision of a monograph complying to the Dutch standard operating procedure by Germany. This pilot has shown the feasibility of work-sharing in developing and updating drug monographs.

Conclusion

The Dutch framework has successfully been extended to the German situation. Work-sharing on the development of dosing recommendations is feasible. Similar extension to Norwegian and Austrian nation-wide formularies has started.

References

van der Zanden T, De Wildt S, Liem T, Offringa M, de Hoog M. Developing a pediatric formulary for the netherlands. Arch Dis Child 2017;Apr;102(4):357–61.

Disclosure(s)

Tjitske van der Zanden is managing director of the Dutch Paediatric Pharmacotherapy Expertise Network; Saskia de Wildt is medical director of Dutch Paediatric Pharmacotherapy Expertise Network. The other authors have no financial disclosures relevant to this article.
P111 Developmental pharmacogenetics of CYP2D6 in Chinese children: loratadine as a probe drug
Authors: Li Q , Y-E Wu , Wang K , Shi H-Y , 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

Although the understanding of CYP2D6 developmental pharmacogenetics in children has made great progress, the current findings are mainly focused on Caucasian children. Given the clear ethnicity difference of CYP2D6 pharmacogenetic profile, there are still unmet needs in understanding developmental pharmacogenetics in inter-ethnic population. We sought to use loratadine as a probe drug to evaluate the effects of ontogeny and pharmacogenetics on the developmental pattern of CYP2D6 in Chinese paediatric patients.

Methods

Chinese children receiving loratadine treatment were enrolled in the present study. The metabolic ratio (MR) of loratadine converted to desloratadine [desloratadine concentrations/loratadine concentrations] of trough concentrations samples at steady-state condition was used as a surrogate of CYP2D6 activity. Loratadine and desloratadine were determined by LC/MS/MS method and variants of CYP2D6 were genotyped.

Results

A total of 40 patients were available for final analysis. The mean age was 4.6 (range 0.5–9.0) years and the mean weight was 19.9 (range 9.0- 42.0) kg. The MR was significantly higher in homozygous wild-type subjects compared with CYP2D6*10 subjects (16.94±14.12 versus 9.37±7.54, p = 0.028). Weight was also found to be significantly corrected with MR (p = 0.030).

Conclusions

The developmental pharmacogenetics of CYP2D6 in Chinese children was evaluated using loratadine as a probe drug. Weight and CYP2D6 genotype showed independently significant impacts on MR.

Disclosure(s)

Nothing to disclose.
P112 Prediction of free Ceftriaxone concentration in children: disease and maturation do matter
Authors: Shi H-Y , Huang X , Li Q , Y-E Wu , Khan MW , Zhou Y , Zheng Y , Hao G-X , Yang X-M , Yang Y-L , Jacqz-Aigrain E , Cui Y-M , Zhao W
Published: May 2019

Background

To evaluate the predictive ability of the existing formula to measure free ceftriaxone levels in children, and optimize the formula by adding disease and maturation factors.

Methods

Fifty children receiving ceftriaxone were evaluated, and the predictive performance of the different equations were assessed by mean absolute error (MAE), mean prediction error (MPE) and linear regression of predicted vs. actual free levels.

Results

The average free ceftriaxone concentration was 2.11 ± 9.51µg/ml. The predicted free concentration was 1.15 ± 4.39µg/ml with the in vivo binding equation, which increased to 1.58 ± 7.73µg/ml and 2.01 ± 9.53µg/ml when adjusted for age (disease adapted equation), and age and albumin (disease-maturation equation) respectively. The average MAE values were 0.48 (in vivo banding equation), 0.34 (disease adapted equation) and 0.41 (disease maturation equation). The average MPE values were -0.41 (in vivo binding equation), 0.14 (disease adapted equation) and 0.09 (disease maturation equation). The respective linear regression equations and coefficients were y=1.8647x+1.0731(R2=0.7398), y=1.1455x+0.8414(R2=0.8674), and y=0.9664x(R2=0.8641) for the in vivo binding, disease adapted and disease maturation equations respectively.

Conclusion

Compared to the in vivo binding equation, the disease adapted and disease maturation equations showed lower MAE and MPE values, and the latter showed the lowest MPE value. In addition, the slope of the disease maturation equation was closer to 1 compared to the other two. Therefore, the optimized disease maturation equation should be used to measure free ceftriaxone levels in children.

Disclosure(s)

Nothing to disclose.